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Current Research and Scholarly Interests

Dr. Suppes is the Director of the Bipolar and Depression Research Program at the VA Palo Alto Health Care System. She is a recognized expert on the biology and treatment of bipolar disorder. Her areas of specific expertise include long-term treatment strategies for bipolar disorder, identification and treatment of bipolar II disorder, treatment of those with bipolar disorders and co-morbid conditions, and use of complementary medicine for bipolar disorder. Dr. Suppes has been integrally involved in numerous initiatives to improve evidence-based treatment for bipolar disorders, including chairing the VA/DOD guidelines for bipolar disorder and the Bipolar module of the Texas Medication Algorithm Project. Dr. Suppes recently completed work on updating the APA DMS-5 criteria for Bipolar and Related Disorders. Her current studies include use of the internet as a tool to support individuals with bipolar disorder and appropriate management of treatment-resistant major depression.

Clinical Trials

The purpose of this study is to detect genetic associations for the development of
schizophrenia (SZ) and bipolar illness (BP) by comparing Veterans with these diseases to
"psychiatrically healthy" Veterans from Veterans Health Administration medical centers. In
addition, the genetic basis for functional capacity and disability in Veterans affected with
SZ and BP will be assessed, as will genetic predictors of suicidality and tardive dyskinesia.
Finally, we will also establish a repository which allows for future genomic studies related
to SZ, BP, and related disorders or sequelae.

The overall purpose is to determine research based 'next-steps' for outpatients with major
depressive disorder who have not had satisfactory outcomes to standard 'first-step'
treatments. The primary objective is to compare the acute (up to 12 weeks) treatment
effectiveness of augmenting an antidepressant with aripiprazole or with bupropion-SR vs.
switching treatment to bupropion-SR monotherapy on symptom remission in Veterans with Major
Depressive Disorder (MDD) who have not achieved optimal response after an adequate trial on
antidepressant (SSRI or SNRI or mirtazapine) monotherapy. The secondary objectives are to
compare the acute (up to 12 weeks) and long term (up to 36 weeks) efficacy, safety, effects
on functioning, suicidality, quality of life, anxiety and other associated symptoms, costs
and cost-effectiveness of each of the three treatments.

Abstract

Medical illnesses are highly comorbid with bipolar disorder, but their relationship to illness characteristics has not been previously delineated.The incidence of 34 medical conditions and 6 poor prognosis factors (PPFs) was derived from answers to a questionnaire in over 900 outpatients with bipolar disorder who gave informed consent. The relationship of PPFs to the number of medical comorbidities was examined by Mann-Whitney U, Pearson r, and logistic regression.When examined individually, each of the 6 PPFs associated with an adverse course of bipolar disorder was significantly related to the number of medical comorbidities patients had. When age, gender, and independence of their relationships to each other were controlled for via regression, 3 of the PPFs remained significant (anxiety disorder, childhood abuse, and age of onset), and having 20 or more prior episodes was a strong trend. The number of PPFs was correlated with the number of comorbidities, although the above 3 PPFs show a similar magnitude of relationship.A history of childhood adversity, early age of onset of bipolar disorder, and an anxiety comorbidity were independently related to the number of medical comorbidities that patients experienced as adults. While the nature and mechanisms of this linkage remain to be further explored, the findings indicate the need for greater attention to and treatment of these 3 PPFs in hopes of ameliorating both the adverse course of bipolar illness and the burden of medical comorbidities with which they are associated.

Abstract

Background: To evaluate the effectiveness of quetiapine extended release once daily in bipolar depression. Methods: Double-blind, placebo-controlled study in acutely depressed adults with bipolar I or II disorder, with or without rapid cycling.Patients were randomized to 8 weeks of quetiapine extended release(XR) 300 mg daily monotherapy or placebo.The primary out come measure was changed from baseline to Week 8 in MADRS total score. Results: Quetiapine XR 300 mg once daily(N=133)showed significantly greater improvement in depressive symptoms compared with placebo (N=137) from Week 1(p<0.001)through to Week 8 (p<0.001).Mean change in MADRS total score at Week 8 was 17.4 in the quetiapine XR group and -11.9 in the placebo group(p<0.001). Response (? 50% reduction in MADRS total score)and remission (MADRS total score ?12)rates at Week 8 were significantly higher with quetiapine XR compared with placebo (p<0.001 and p<0.05, respectively).Quetiapine XR improved core symptoms of depression. The most common adverse events associated with quetiapine XR were dry mouth, somnolence,and sedation. Greater weight gain was observed inpatients on quetiapine XR relative to placebo. Limitations: Fewer patients with bipolar II disorder included, only one fixed dose tested and the lack of an active comparator. Conclusions: Quetiapine XR(300 mg)once daily monotherapy was significantly more effective than placebo for treating episodes of depression in bipolar I disorder, throughout the 8-week study,with significance observed as early as Day 7.Adverse events were consistent with the known effects of quetiapine.

Abstract

Early-onset bipolar (BP) disorder and other poor prognosis characteristics are more prevalent in patients from the United States than from the Netherlands and Germany (abbreviated as Europe). We explored the impact of parental loading for affective illness on onset and other characteristics of BP disorder.Parental history for unipolar (UP) and bipolar (BP) depression and course of illness characteristics were obtained from self-report in adults (average age 42) with BP disorder. Illness characteristics were examined by ?(2) and multinomial logistic regression in relationship to the degree of parental loading: i) both parents negative; ii) one UP disorder; iii) one with BP disorder; and iv) both affected.After controlling for many poor prognosis factors, compared with those from Europe, patients from the United States had more iii) one parent with BP disorder and iv) both parents affected. An early age of onset of BP disorder was independently associated with this increased parental loading for affective disorder.Parental history of BP disorder and both parents with a mood disorder were more common in the United States than Europe and were associated with an early onset of bipolar disorder and other poor prognosis characteristics. These findings deserve replication and exploration of the potential mechanisms involved and their therapeutic implications.

Abstract

There is some controversy but growing evidence that childhood onset bipolar disorder may be more prevalent and run a more difficult course in the United States than some European countries.We update and synthesize course of illness data from more than 960 outpatients with bipolar disorder (average age 40) from 4 sites in the U.S. and 3 sites in Netherlands and Germany. After giving informed consent, patients reported on parental history, childhood and lifetime stressors, comorbidities, and illness characteristics.Almost all aspects of bipolar disorder were more adverse in patients from the US compared with Europe, including a significantly higher prevalence of: bipolar disorder in one parent and a mood disorder in both parents; childhood verbal, physical, or sexual abuse; stressors in the year prior to illness onset and the last episode; childhood onsets of bipolar illness; delay to first treatment; anxiety disorder, substance abuse, and medical comorbidity; mood episodes and rapid cycling; and nonresponse to prospective naturalistic treatment.Selection bias in the recruit of patients cannot be ruled out, but convergent data in the literature suggest that this does not account for the findings. Potential mechanisms for the early onset and more adverse course in the U.S. have not been adequately delineated and require further investigation.The data suggest the need for earlier and more effective long-term treatment intervention in an attempt to ameliorate this adverse course and its associated heavy burden of psychiatric and medical morbidity.

Abstract

The aim of this study was to test the relationships between mood state and rhythm disturbances as measured via actigraphy in bipolar disorder by assessing the correlations between manic and depressive symptoms as measured via Young Mania Rating Scale (YMRS) and 30-item Inventory for Depressive Symptomatology, Clinician-Rated (IDS-C-30) scores and the actigraphic measurements of rhythm, the 24-hour autocorrelation coefficient and circadian quotient.The research was conducted at the University of Texas Southwestern Medical Center at Dallas from February 2, 2009, to March 30, 2010. 42 patients with a DSM-IV-TR diagnosis of bipolar I disorder were included in the study. YMRS and the IDS-C-30 were used to determine symptom severity. Subjects wore the actigraph continuously for 7 days. The 24-hour autocorrelation coefficient was used as an indicator of overall rhythmicity. The circadian quotient was used to characterize the strength of a circadian rhythm.A greater severity of manic symptoms correlated with a lower degree of rhythmicity and less robust rhythms of locomotor activity as indicated by lower 24-hour autocorrelation (r = -0.3406, P = .03) and circadian quotient (r = -0.5485, P = .0002) variables, respectively. No relationship was noted between the degree of depression and 24-hour autocorrelation scores (r = -0.1190, P = .45) or circadian quotient (r = 0.0083, P = .96). Correlation was noted between the 24-hour autocorrelation and circadian quotient scores (r = 0.6347, P < .0001).These results support the notion that circadian rhythm disturbances are associated with bipolar disorder and that these disturbances may be associated with clinical signatures of the disorder. Further assessment of rhythm disturbances in bipolar disorder is warranted.

Abstract

Medical comorbidities are common in patients with bipolar (BP) disorder but have not been previously examined for differences between United States and Europe. More than 900 outpatients with BP I and BP II disorder (mean age, 41 years) filled out a questionnaire including the occurrence of 30 listed medical conditions. The patients from the United States were from Los Angeles, Dallas, Cincinnati, and Bethesda, whereas those from Europe were from Utrecht, Freiberg, and Munich. Those from the United States had a significantly higher incidence of obesity and nine other medical comorbidities than those from Europe, who had only more cases of hyperthyroidism. The burden of medical comorbidities in patients with BP disorder from the United States seems higher than in patients from Europe. Given the adversities, morbidity, and early mortality associated with these conditions and their interaction with the morbidity and lethality of BP disorder itself, greater efforts at treatment and prevention of these medical comorbidities would seem indicated.

Abstract

Bipolar disorder often co-occurs with anxiety disorders. Evidence suggests that second-generation antipsychotics (SGAs) may be useful in treating both conditions. This study examined the efficacy of ziprasidone in the treatment of these disorders.This 3-site, randomized, double-blind, placebo-controlled, parallel group, 8-week trial of ziprasidone monotherapy examined 49 subjects with bipolar disorder and lifetime panic disorder (with or without agoraphobia) or generalized anxiety disorder (GAD) experiencing moderately severe anxiety symptoms at entrance into the study. Both bipolar disorder and anxiety diagnoses were based on DSM-IV-TR criteria. Patients were screened and randomized from June 25, 2010, through August 23, 2011. Primary outcome measures were the Clinical Global Impressions-21 Anxiety Scale (CGI-21 Anxiety) and the Sheehan Disability Scale (SDS), with secondary measures monitoring anxiety and mood symptoms.Last-observation-carried-forward analyses demonstrated that patients in the ziprasidone group did not improve significantly more than those in the placebo group on the CGI-21 Anxiety (F1 = 0.34; P = .564) or SDS (F1 = 0.26; P = .611). Secondary analysis using hierarchical linear modeling found similar results (CGI-21 Anxiety: F1 = 1.82; P = .178; and SDS: F1 = 0.70; P = .408). Regardless of group, time in the study was associated with significant decrease in anxiety (F1 = 11.08; P = .001) and total disability (F1 = 26.16; P < .001). Patients in the ziprasidone group showed a greater increase in abnormal involuntary movement, and 81.8% (n = 9) of the subjects who withdrew from the study due to adverse events, serious adverse events, or side effects were in the ziprasidone group.Results suggest that ziprasidone monotherapy was not associated with a clinically significant improvement in anxiety symptoms or improved function for patients with bipolar disorder, lifetime panic disorder or GAD, and concurrent moderately severe anxiety symptoms, and it was associated with a more negative side-effect profile relative to placebo.ClinicalTrials.gov identifier: NCT01172652.

Abstract

Many patients with bipolar disorder in the United States experience a deteriorating course of illness despite naturalistic treatment in the community. We examined a variety of factors associated with this pattern of illness progression.From 1995 to 2002, we studied 634 adult outpatients with bipolar disorder (mean age of 40 years) emanating from 4 sites in the United States. Patients gave informed consent and completed a detailed questionnaire about demographic, vulnerability, and course-of-illness factors and indicated whether their illness had shown a pattern of increasing frequency or severity of manic or depressive episodes. Fifteen factors previously linked in the literature to a poor outcome were examined for their relationship to illness progression using Kruskal-Wallis test, followed by a 2-sample Wilcoxon rank sum (Mann-Whitney) test, ?(2), and logistical regression.All of the putative poor prognosis factors occurred with a high incidence, and, with the exception of obesity, were significantly (P < .05) associated with illness progression. These factors included indicators of genetic and psychosocial risk and loss of social support, early onset, long delay to first treatment, anxiety and substance abuse comorbidity, rapid cycling in any year, and the occurrence of more than 20 prior episodes prior to entering the network. A greater number of factors were linearly associated with the likelihood of a progressively worsening course.Multiple genetic, psychosocial, and illness factors were associated with a deteriorating course of bipolar disorder from onset to study entry in adulthood. The identification of these factors provides important targets for earlier and more effective therapeutic intervention in the hope of achieving a more benign course of bipolar disorder.

Abstract

Considerable data suggest that compared to some European countries, in the U.S. there are more childhood onset bipolar disorders, more adverse courses of illness, and greater treatment resistance. Psychosocial variables related to these findings have not been adequately explored. Therefore we analyzed psychosocial stressors in three time domains: childhood; the year prior to illness Onset; and the Last Episode from questionnaires in 968 outpatients (mean age 41) with bipolar I or II disorder; 676 from four sites in the U.S. and 292 from three in the Netherlands and Germany (abbreviated here as Europe). Compared to the Europeans, those from the U.S. had significantly more stressors in childhood and prior to the last episode. Stressors prior to the last episode were related to: childhood stressors; an earlier age at illness onset; anxiety and substance abuse comorbidity; lower income; both parents having an affective illness; and feeling more stigma. These data suggest a greater prevalence of adverse life events in childhood and over the course of bipolar illness in the U.S. compared to the Netherlands and Germany. Clinical, therapeutic, and public health approaches to these illness-relevant stressors require further exploration.

MAINTENANCE TREATMENT WITH QUETIAPINE WHEN COMBINED WITH EITHER LITHIUM OR DIVALPROEX IN BIPOLAR I DISORDER: ANALYSIS OF TWO LARGE RANDOMIZED, PLACEBO-CONTROLLED TRIALSDEPRESSION AND ANXIETYSuppes, T., Vieta, E., Gustafsson, U., Ekholm, B.2013; 30 (11): 1089-1098

Abstract

BACKGROUND: To determine the efficacy and safety of quetiapine combined with lithium or divalproex for preventing mood events in patients with bipolar I disorder. In this pooled analysis of two similar long-term studies (D1447C00126 [NCT00107731] and D1447C00127 [NCT00081380]), lithium and divalproex treatment groups were analyzed separately. METHODS: Patients received open-label quetiapine (400-800 mg/d) plus lithium or divalproex to achieve ?12 weeks of clinical stability before being randomized to double-blind combination treatment with quetiapine (400-800 mg/d) or placebo plus lithium or divalproex for up to 104 weeks. The primary endpoint was time to first mood event postrandomization following open stabilization. RESULTS: Of 3,414 patients in the stabilization phase, 1,326 were randomized. There were no differences in the risk of recurrence of mood, mania, or depression between quetiapine plus lithium or quetiapine plus divalproex. Among patients co-treated with placebo and lithium, the risk of recurrence of a mania event was significantly higher than among patients co-treated with placebo and divalproex. In patients with an index episode of mania, placebo plus lithium was associated with a significantly higher risk of recurrence of a mania event than placebo plus divalproex. Safety data were generally consistent with recognized safety profiles. CONCLUSIONS: In patients with bipolar I disorder previously stabilized on quetiapine and lithium or divalproex, maintenance therapy with quetiapine significantly increased the time to recurrence of a mood event (mania or depression) versus placebo, regardless of whether it was combined with lithium or divalproex.

Abstract

BACKGROUND: Co-occurring psychiatric diagnoses have a negative impact on quality of life and change the presentation and prognosis of bipolar disorder (BD). To date, comorbidity research on patients with BD has primarily focused on co-occurring anxiety disorders and trauma history; only recently has there been a specific focus on co-occurring PTSD and BD. Although rates of trauma and PTSD are higher in those with bipolar disorder than in the general population, little is known about differences across bipolar subtypes. METHODS: Using the NIMH STEP-BD dataset (N=3158), this study evaluated whether there were baseline differences in the prevalence of PTSD between participants with bipolar disorder I (BDI) and bipolar disorder II (BDII), using the MINI and the Davidson Trauma Scale. Differences in PTSD symptom clusters between patients with BDI and BDII were also evaluated. RESULTS: A significantly greater proportion of participants with BDI had co-occurring PTSD at time of study entry (?(2)(1)=12.6; p

Abstract

OBJECTIVES: To compare the efficacy and safety of adjunctive quetiapine (QTP) versus placebo (PBO) for patients with bipolar II disorder (BDII) currently experiencing mixed hypomanic symptoms in a 2-site, randomized, placebo-controlled, double-blind, 8-week investigation. METHODS: Participants included 55 adults (age 18-65 years) who met criteria for BDII on the Structured Clinical Interview for DSM-IV-TR (SCID). Entrance criteria included a stable medication regimen for ?2 weeks and hypomania with mixed symptoms (>12 on the Young Mania Rating Scale [YMRS] and >15 on the Montgomery Asberg Depression Rating Scale [MADRS] at two consecutive visits 1-3 days apart). Participants were randomly assigned to receive adjunctive quetiapine (n=30) or placebo (n=25). RESULTS: Adjunctive quetiapine demonstrated significantly greater improvement than placebo in Clinical Global Impression for Bipolar Disorder Overall Severity scores (F(1)=10.12, p=.002) and MADRS scores (F(1)=6.93, p=.0138), but no significant differences were observed for YMRS scores (F(1)=3.68, p=.069). Side effects of quetiapine were consistent with those observed in previous clinical trials, with sedation/somnolence being the most common, occurring in 53.3% with QTP and 20.0% with PBO. CONCLUSIONS: While QTP was significantly more effective than PBO for overall and depressive symptoms of BDII, there was no significant difference between groups in reducing symptoms of hypomania. Hypomania improved across both groups throughout the study.

Abstract

Sleep disturbance is a core feature of bipolar disorder. To date there are a limited number of studies that compare subjective and objective measures of sleep in populations of subjects with mood disorders. This study evaluated the relationship between subjective and objective measurements of total sleep time (TST) in a bipolar type I disorder (BD I) population.Thirty-nine subjects diagnosed with BD I participated in the study. Mood symptoms were assessed via YMRS and IDS-30-C. Subjects wore an actigraph device and maintained a sleep diary for seven consecutive days. Differences between TST as estimated via sleep diaries and actigraphy were calculated.Objective and subjective measures of TST were significantly correlated (r=0.5151, p=0.0008). Secondary analysis revealed that the severity of depressive symptoms did correlate to this discrepancy (t=2.65, p=0.01).The impact that medications have on the accuracy of TST reported was not investigated. Also, sleep diaries may have acted to prompt subjects to pay closer attention to their sleep habits and therefore more accurately report TST than in the average clinical setting.The results of the current study demonstrate a significant correlation between the estimation of TST as measured objectively via actigraphy and subjectively via sleep diaries in BD patients. Mood symptomotology might impact the accuracy of TST reported. Further study is warranted.

Abstract

A role for childhood adversity in the development of numerous medical conditions in adults has been described in the general population, but has not been examined in patients with bipolar disorder who have multiple medical comorbidities which contribute to their premature mortality.More than 900 outpatients (average age 41) with bipolar disorder completed questionnaires that included information about the occurrence of verbal, physical, or sexual abuse in childhood and whether their parents had a mood or substance abuse disorder, or a history of suicidality. These factors were combined to form a total childhood adversity score, which was then related to one or more of 30 medical conditions patients rated as present or absent.The child adversity score was significantly related to the total number of medical comorbidities a patient had (p

Abstract

Clinical characteristics predicting response and remission to psychopharmacological treatment of bipolar disorder (BD) and co-occurring anxiety disorders have been understudied. We hypothesized that non-response to risperidone or placebo in individuals with co-occurring BD and anxiety symptoms would be associated with a more severe clinical course of BD, and certain demographic variables. This study was a secondary analysis of a randomized, double-blind, parallel, 8-week study comparing risperidone monotherapy and placebo in individuals with BD plus current panic disorder, current generalized anxiety disorder (GAD), or lifetime panic disorder (n=111) [31]. We compared clinical characteristics of responders (50% improvement on the Hamilton Anxiety Scale [HAM-A]) and non-responders as well as remitters (HAM-A<7) and non-remitters in risperidone treatment (n=54) and placebo (n=57) groups. For non-responders in the risperidone group, co-occurring lifetime panic disorder was significantly more common than for non-responders in the placebo group. Apart from this, no significant differences in course of illness or demographics were found either between or across groups for patients with BD and co-occurring anxiety symptoms receiving risperidone or placebo in this acute phase study.

Abstract

Anxiety disorders complicate the treatment of bipolar disorder but are seldom the focus of bipolar treatment studies.The anxiolytic effect of quetiapine XR 50-300 mg/day compared to divalproex ER (500-3000 mg/day) was tested in an 8-week, double-blind, placebo-controlled, randomized clinical trial in 149 patients with bipolar disorder and a co-occurring panic disorder or GAD. The primary efficacy measure was the Clinician Global Improvement-21 Anxiety Scale (CGI-21). Secondary measures included the Hamilton Anxiety Scale (HAM-A) and Sheehan Panic Disorder Scale (SPS).Repeated measures last-observation-carried-forward (LOCF) analyses of variance demonstrated significant treatment-by-time interaction effects on 3 of the 4 anxiety measures. Quetiapine XR at a mean endpoint dose of 186 mg/day produced rapid sustained improvements relative to baseline, divalproex ER and placebo on anxiety. Mean baseline-to-endpoint improvement was significantly greater for quetiapine XR compared to divalproex ER and placebo on the HAM-A and SPS. Both active medications were well tolerated, but weight gain was higher on quetiapine XR.The study was limited to 8 weeks and to patients with bipolar disorder and comorbid panic disorder or GAD. The results may not be applicable to quetiapine XR as an add-on treatment to mood stabilizers or to bipolar disorder comorbid with other anxiety disorders.Quetiapine XR in a dose range of 50-300 mg/day appears to reduce anxiety in bipolar patients with comorbid panic disorder or GAD treated for 8 weeks. The efficacy of other second-generation antipsychotics and mood stabilizers in patients with bipolar disorder and a co-occurring anxiety disorder should be investigated in double-blind, placebo-controlled studies.

Abstract

Manic episodes are heterogeneous. Mixed states may differ in important clinical characteristics from other manic episodes. However, it has not been established whether mixed states are a distinct type of episodes, or a common basic structure exists across manic episodes.Using 2179 well-characterized subjects in the pretreatment phase of six randomized, clinical trials, we conducted rotated factor analysis followed by cluster analysis, using all items from the Young Mania Rating Scale and the Montgomery-┼sberg Depression Scale. Analyses were conducted for all subjects (n=2179) and for those in Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) mixed (n=644) and non-mixed (n=1535) episodes separately.There were five factors characterized (in order of variance accounted for) as depression, mania, sleep disturbance, judgment/impulsivity and irritability/hostility. Cluster analysis identified five clusters. Three were predominately manic, with depression scores below average for the overall group. Two had high average depression scores; these clusters differed in irritability/hostility. Judgment/impulsivity scores were similar across factors. Essentially identical factors and clusters existed whether analyses were done in all subjects or only in subjects classified by DSM-IV as mixed or non-mixed.Exclusion criteria of studies may limit generalizability of findings.All manic episodes, whether mixed or non-mixed, shared a similar structure according to factor/cluster analysis. Patients with high depression factor scores were heterogeneous with respect to irritability. These data suggest that depressive symptoms should be considered a dimensional property across manic episodes, rather than as defining a specific type of episode.

Abstract

The fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) opted to retain existing diagnostic boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia. The debate preceding this decision focused on understanding the biologic basis of these major mental illnesses. Evidence from genetics, neuroscience, and pharmacotherapeutics informed the DSM-5 development process. The following discussion will emphasize some of the key factors at the forefront of the debate.Family studies suggest a clear genetic link between bipolar I disorder, schizoaffective disorder, and schizophrenia. However, large-scale genome-wide association studies have not been successful in identifying susceptibility genes that make substantial etiological contributions. Boundaries between psychotic disorders are not further clarified by looking at brain morphology. The fact that symptoms of bipolar I disorder, but not schizophrenia, are often responsive to medications such as lithium and other anticonvulsants must be interpreted within a larger framework of biological research.For DSM-5, existing nosological boundaries between bipolar I disorder and schizophrenia were retained and schizoaffective disorder preserved as an independent diagnosis since the biological data are not yet compelling enough to justify a move to a more neurodevelopmentally continuous model of psychosis.

Abstract

Episodes of bipolar disorder are defined as depressive or manic, but depressive and manic symptoms can combine in the same episode. Coexistence or rapid alternation of depressive and manic symptoms in the same episode may indicate a more severe form of bipolar disorder and may pose diagnostic and treatment challenges. However, definitions of mixed states, especially those with prominent depression, are not well established.The authors performed literature searches for bipolar disorder, multivariate analyses, and the appearance of the terms "mixed" in any field; references selected from the articles found after the search were combined after a series of conferences among the authors.The authors reviewed the evolution of the concept of mixed states and examined the symptom structure of mixed states studied as predominantly manic, predominantly depressive, and across both manic and depressive episodes, showing essentially parallel structures of mixed states based on manic or depressive episodes. The authors analyzed the relationships between mixed states and a severely recurrent course of illness in bipolar disorder, with early onset and increased co-occurring anxiety-, stress-, and substance-related disorders, and they used this information to derive proposed diagnostic criteria for research or clinical use.The definitions and properties of mixed states have generated controversy, but the stability of their characteristics over a range of clinical definitions and diagnostic methods shows that the concept of mixed states is robust. Distinct characteristics related to the course of illness emerge at relatively modest opposite polarity symptom levels in depressive or manic episodes.

Abstract

The long-term impact of prior antidepressant exposure on the subsequent course of bipolar illness remains controversial.139 outpatients (mean age, 42 years) with bipolar I disorder diagnosed by DSM-IV criteria had a detailed retrospective examination of their prior course of illness on the National Institute of Mental Health Life Chart Method. Number of prior antidepressant trials and total duration of antidepressant exposure were assessed. Prospective long-term response (for at least 6 months) to naturalistic treatment in the network from 1996 through 2002 was the primary outcome measure as it related to prior antidepressant exposure (and other illness variables) by logistic regression, with P < .05 used for statistical significance in this post hoc analysis.Greater number of antidepressant trials, but not duration of antidepressant exposure, was related to prospective nonresponse (P = .0051) whether or not antidepressants were covered by concurrent treatment with a mood stabilizer or atypical antipsychotic. Poor prospective response was also independently related to having had an anxiety disorder and 20 or more prior affective episodes.That the number of antidepressant trials, but not duration of antidepressant treatment, was associated with prospective nonresponse suggests that it is the repeated use of antidepressants to treat episodes of depression that is related to poor prospective response to naturalistic treatment. The direction of causality is unclear as to whether more antidepressant trials led to this increased treatment resistance or whether a difficult course of illness with more episodes and anxiety comorbidity engendered more attempts at antidepressant treatment.

Abstract

Studies have shown that patients with bipolar disorder have high rates of serious and/or untreated co-occurring general medical conditions. This case series examined reports of co-occurring medical conditions with bipolar disorder in potential clinical study participants, and in particular the percentage of these individuals who were previously unaware of their conditions.Patients were potential participants in 1 of 2 medication trials who met DSM-IV criteria for bipolar disorder and were excluded from those studies just prior to randomization from May 2009 through July 2011. Patients were compared with each other on a number of demographic criteria, including age, race, gender, reason for exclusion from the trial, and psychiatric diagnoses.Of the patients excluded from the studies just prior to randomization, 31% (n = 10) were excluded because of medical conditions previously unreported by the patient during screening for these studies. Seventy percent of those excluded patients (n = 7) had no prior knowledge of their conditions.These results suggest that patients with bipolar disorder may not only have high rates of co-occurring medical conditions but also frequently remain unaware of those conditions. These findings indicate that co-occurring general medical conditions may be a more serious problem in the treatment of bipolar disorder than previously appreciated and that more stringent monitoring and guidelines are needed regardless of medication regimen. This case series asserts that, regardless of a patient's claim of having no medical conditions, more general medical screening may be needed in outpatient psychiatric settings.

Abstract

Increased early-onset bipolar illness was seen in the US compared with the Netherlands and Germany (abbreviated here as Europe), but other clinical characteristics, medication use, and treatment response have not been systematically explored. Outpatients with bipolar disorder were treated naturalistically and followed prospectively at four sites in the US and three in Europe. Data and clinical characteristics were collected from patient questionnaires, and medication usage and good-to-excellent response to treatment for at least 6 months ascertained from daily clinician ratings on the National Institutes of Mental Health-Life Chart Method. Almost all clinical characteristics earlier associated with a poor treatment response were more prevalent in the US than in Europe, including early onset, environmental adversity, rapid cycling, more than 20 prior episodes, comorbid anxiety and substance abuse disorders, and a positive parental history for an affective disorder. Lithium was used more frequently in Europe than in the US and had a higher rate of success, whereas valproate was used more in the US, with a trend toward higher success in Europe. Antidepressants were used more in the US, but had extremely low success rates. Many other agents were deployed differently on the two continents, but success rates were consistently lower in the US than in Europe. In conclusion, clinical characteristics and patterns of medication usage and effectiveness differed markedly in the two continents suggesting the need for uncovering explanations and considering the two populations as heterogeneous in the future pharmacological studies.

Abstract

Relatively little is known about the co-occurrence of bipolar and eating disorders. We therefore assessed the prevalence and clinical correlates of eating disorders in 875 patients with bipolar disorder.875 outpatients with DSM-IV bipolar I or II disorder were evaluated with structured diagnostic interviews and clinician- and self-administered questionnaires to determine bipolar and eating disorder diagnoses, other comorbid Axis I disorder diagnoses, and demographic and historical illness characteristics.125 (14.3%) patients met DSM-IV criteria for at least one comorbid lifetime Axis I eating disorder, with binge eating disorder (N=77) being more common than bulimia nervosa (n=42) and anorexia nervosa (N=27). There were no significant eating disorder comorbidity differences between bipolar I and bipolar II patients. Presence of a lifetime comorbid eating disorder was associated with female gender, younger age, earlier age of onset of mood symptoms and of bipolar disorder, presentation in a mixed episode, greater number of prior mood episodes, history of rapid cycling and suicide attempts, greater mean BMI, obesity and severe obesity, and family history of depression, bipolar disorder, alcoholism, and drug abuse. When the three eating disorder groups were compared, lifetime anorexia nervosa was associated with normal weight and a lifetime anxiety disorder, lifetime bulimia nervosa was associated with overweight, and lifetime binge eating disorder was associated with obesity and severe obesity.Patients with bipolar disorder, especially women, not infrequently have comorbid eating disorders, and this comorbidity is associated with an earlier age of onset and more severe course of bipolar illness.

Abstract

Recently, the 9(th) International Conference on Bipolar Disorder (ICBD) took place in Pittsburgh, PA, June 9-11, 2011. The conference focused on a number of important issues concerning the diagnosis of bipolar disorders across the life span, advances in neuroscience, treatment strategies for bipolar disorders, early intervention, and medical comorbidity. Several of these topics were discussed in four plenary sessions. This meeting report describes the major points of each of these sessions and included (1) strategies for moving biology forward; (2) bipolar disorder and the forthcoming new DSM-5 nomenclature; (3) management of bipolar disorders-both theory and intervention, with an emphasis on the medical comorbidities; and, (4) a review of several key task force reports commissioned by the International Society for Bipolar Disorder (ISBD).

Abstract

To evaluate the clinical correlates of and types of naturalistic treatments associated with sustained improvement/remission for at least 6 months in outpatients with bipolar disorder.Five hundred twenty-five outpatients with bipolar disorder (77.7% bipolar I) gave informed consent, had their mood rated daily on the National Institute of Mental Health Life Chart Method for a minimum of at least 1 year, and recorded all medications. Demographics and clinical characteristics of patients with a "sustained response" (ratings of "improved" or "very much improved" on the Clinical Global Impressions-Bipolar Version for a period of at least 6 months) versus nonresponders were compared. The study was conducted from 1996 to 2002.Of the 429 patients who were ill at study entry, 195 (45.5%) showed a sustained response; 54.5% showed no or insufficient response. A mean of 2.98 medications was given at time of improvement, which occurred after a mean of 18 months of participation in the study. Lithium and valproate were the medications most frequently prescribed at the time of improvement and had among the highest overall success rates. Equally complex regimens were employed in the nonresponders who, however, had a more adverse clinical course prior to network entry. Nonresponders were ultimately exposed to more antidepressants and antipsychotics than the sustained responders.A mean of 1.5 years and at times highly complex medication regimens were required to achieve a sustained response for 6 months during naturalistic outpatient treatment of bipolar disorder. Delineating the clinical and biologic correlates of individual response to combination treatment is a very high clinical research priority, as is developing new treatment strategies for the large proportion of patients who fail to respond in a sustained fashion.

Abstract

We examined the influence of age at onset of illness and the delay in time to first treatment on morbidity in adulthood.529 adult outpatients with a mean age of 42 years, who entered our research network from 1996 through 2001 and who were diagnosed with bipolar disorder according to DSM-IV criteria, were rated prospectively on a daily basis with the National Institute of Mental Health-Life Chart Method during naturalistic treatment for up to 4 years.Fifty percent of patients had illness onset in childhood (<13 years of age) or adolescence (13-18 years of age). In year 1 of follow-up, these patients, compared to those with adult onset, showed significantly (P

Abstract

The authors assessed gender differences in the proportion of clinical visits spent depressed, manic, or euthymic in patients with bipolar disorder.Data were analyzed from 711 patients with bipolar I or II disorder who were followed prospectively over 7 years (13,191 visits). The main outcome measures were the presence of symptoms of depression or of hypomania or mania, measured by the Inventory of Depressive Symptomatology and the Young Mania Rating Scale. Data were analyzed using three separate repeated-measures regressions with a logistic link function to model the probability that an individual was depressed, manic, or euthymic. The models controlled for bipolar I or bipolar II diagnosis, rapid cycling, age, time in the study, comorbid anxiety disorders, and comorbid substance use disorders.In approximately half of visits, patients had depressive, manic, or hypomanic symptoms. The likelihood of having depressive symptoms was significantly greater for women than for men. This was accounted for by higher rates in women of rapid cycling and anxiety disorders, each of which was associated with increased rates of depression. All patient groups showed an increase in number of euthymic visits and a decrease in number of visits with depressive and manic symptoms with increased time in study.Bipolar patients spend a substantial proportion of their time ill. Significant gender differences exist, with women spending a greater proportion of their visits in the depressive pole. This finding appears to be related to the corresponding differences in rates of rapid cycling and anxiety disorders.

Abstract

The clinical and self-report versions of the Quick Inventory of Depressive Symptomatology (QIDS-C16 and QIDS-SR16) have been well studied in patients with major depressive disorder and in one recent study using patients with bipolar disorder. This article examines these measures in a second sample of 141 outpatients with bipolar disorder in different phases of the illness.At baseline, 61 patients were depressed and 30 were euthymic; at exit, 50 were depressed and 52 were euthymic. The remaining patients (at baseline or exit) were in either a manic or mixed phase and were pooled for statistical reasons.Similar results were found for the QIDS-C16 and QIDS-SR16. Scores were reasonably reliable to the extent that variability within groups permitted. As expected, euthymic patients showed less depressive symptomatology than depressed patients. Sad mood and general interest were the most discriminating symptoms between depressed and euthymic phases. Changes in illness phase (baseline to exit) were associated with substantial changes in scores. The relation of individual depressive symptoms to the overall level of depression was consistent across phases.Both the QIDS-SR16 and QIDS-C16 are suitable measures of depressive symptoms in patients with bipolar disorder.

Abstract

Categorization of psychotic illnesses into schizophrenic and affective psychoses remains an ongoing controversy. Although Kraepelinian subtyping of psychosis was historically beneficial, modern genetic and neurophysiological studies do not support dichotomous conceptualization of psychosis. Evidence suggests that schizophrenia and bipolar disorder rather present a clinical continuum with partially overlapping symptom dimensions, neurophysiology, genetics and treatment responses. Recent large scale genetic studies have produced inconsistent findings and exposed an urgent need for re-thinking phenomenology-based approach in psychiatric research. Epidemiological, linkage and molecular genetic studies, as well as studies in intermediate phenotypes (neurocognitive, neurophysiological and anatomical imaging) in schizophrenia and bipolar disorders are reviewed in order to support a dimensional conceptualization of psychosis. Overlapping and unique genetic and intermediate phenotypic signatures of the two psychoses are comprehensively recapitulated. Alternative strategies which may be implicated into genetic research are discussed.

Abstract

To evaluate the effectiveness of quetiapine extended release once daily in bipolar depression.Double-blind, placebo-controlled study in acutely depressed adults with bipolar I or II disorder, with or without rapid cycling. Patients were randomized to 8 weeks of quetiapine extended release (XR) 300 mg daily monotherapy or placebo. The primary outcome measure was change from baseline to Week 8 in MADRS total score.Quetiapine XR 300 mg once daily (N=133) showed significantly greater improvement in depressive symptoms compared with placebo (N=137) from Week 1 (p<0.001) through to Week 8 (p<0.001). Mean change in MADRS total score at Week 8 was -17.4 in the quetiapine XR group and -11.9 in the placebo group (p<0.001). Response (>or=50 reduction in MADRS total score) and remission (MADRS total score

Abstract

During post-acute phase pharmacotherapy for bipolar disorder, there has been little empirical study to establish when emerging mania symptoms (1) are of clinical significance and (2) reflect iatrogenic events versus the natural course of illness.Secondary analyses were conducted in a previously studied group of bipolar I disorder (DSM-IV) outpatients randomly assigned to lamotrigine monotherapy (n=171) or placebo (n=121), and a larger prerandomization group (N=966) during open-label titration of lamotrigine, following an index depressive episode. Time until the emergence of mania symptoms, at varying severity thresholds, was examined over 6 months for lamotrigine versus placebo, while controlling for potential confounding factors in Cox proportional hazard models. Subject enrollment occurred between July 1997 and August 2001.Rates of mood elevation during both acute open-label and randomized continuation phases of lamotrigine treatment were comparable to those seen with placebo during the randomized phase. The hazard ratio for the emergence of mania symptoms with lamotrigine was not significantly different from placebo (hazard ratio=0.79; 95% CI, 0.53 to 1.16), with an upper bound that suggests no meaningful increase in susceptibility toward mania with lamotrigine. By contrast, clinically meaningful rises in mania symptom severity were predicted by baseline residual manic symptoms prerandomization and by the number of manic, hypomanic, or mixed episodes in the past year.Based on a composite definition of mood destabilization involving a range of severity thresholds for emerging signs of mania, lamotrigine confers no meaningful elevated risk relative to placebo for mood destabilization in bipolar I disorder. Rather, illness burden related to residual or lifetime mania features may hold greater importance for explaining mania relapses or breakthrough manic features during lamotrigine continuation pharmacotherapy.

Abstract

Via an international panel of experts, this paper attempts to document, review, interpret, and propose operational definitions used to describe the course of bipolar disorders for worldwide use, and to disseminate consensus opinion, supported by the existing literature, in order to better predict course and treatment outcomes.Under the auspices of the International Society for Bipolar Disorders, a task force was convened to examine, report, discuss, and integrate findings from the scientific literature related to observational and clinical trial studies in order to reach consensus and propose terminology describing course and outcome in bipolar disorders.Consensus opinion was reached regarding the definition of nine terms (response, remission, recovery, relapse, recurrence, subsyndromal states, predominant polarity, switch, and functional outcome) commonly used to describe course and outcomes in bipolar disorders. Further studies are needed to validate the proposed definitions.Determination and dissemination of a consensus nomenclature serve as the first step toward producing a validated and standardized system to define course and outcome in bipolar disorders in order to identify predictors of outcome and effects of treatment. The task force acknowledges that there is limited validity to the proposed terms, as for the most part they represent a consensus opinion. These definitions need to be validated in existing databases and in future studies, and the primary goals of the task force are to stimulate research on the validity of proposed concepts and further standardize the technical nomenclature.

Abstract

To assess the relationship between depressive relapse and change in thyroid function in an exploratory post hoc analysis from a controlled maintenance evaluation of bipolar I disorder.Mean thyroid-stimulating hormone (TSH) and outcome data were pooled from two 18-month, double-blind, placebo-controlled, maintenance studies of lamotrigine and lithium monotherapy. A post hoc analysis of 109 subjects (n = 55 lamotrigine, n = 32 lithium, n = 22 placebo) with serum TSH values at screening and either week 52 (+/-14 days) or study drop-out was conducted.Lithium-treated subjects who required an intervention for a depressive episode had a significantly higher adjusted mean TSH level (4.4 microIU/ml) compared with lithium-treated subjects who did not require intervention for a depressive episode (2.4 microIU/ml).Lithium-related changes in thyroid function are clinically relevant and should be carefully monitored in the maintenance phase of bipolar disorder to maximize mood stability and minimize the risk of subsyndromal or syndromal depressive relapse.

Abstract

The treatment of bipolar disorder is often complicated by the presence of a co-occuring anxiety disorder. Although second generation antipsychotics are being used with increasing frequency in bipolar patients, their anxiolytic effects have not been well studied in this population.The anxiolytic effect of risperidone 0.5-4 mg/day was tested in an 8-week, double-blind, placebo-controlled, randomized clinical trial in 111 patients with bipolar disorder and a co-occuring panic disorder or generalized anxiety disorder (GAD). The primary outcome measure was the Clinician Global Improvement-21 Anxiety scale (CGI-21 Anxiety). Secondary measures included the Hamilton Anxiety Scale (HAM-A) and the Sheehan Panic Disorder Scale.On the last-observation-carried forward analysis of repeated measures analysis of variance (ANOVA), risperidone was not more effective than placebo for the CGI-21 Anxiety score or the other anxiety outcome measures. Risperidone was well tolerated, with only two patients withdrawing because of adverse events.The risperidone treated group had more patients with mixed states and lifetime panic disorder at randomization than the placebo group. The study was limited to 8 weeks and to individuals with bipolar and comorbid panic disorder or GAD. The results may not be applicable to risperidone as an add-on treatment to mood stabilizers, or to bipolar disorder comorbid with anxiety disorders other than panic disorder or GAD.Risperidone monotherapy was not an effective anxiolytic for bipolar patients with comorbid panic disorder or GAD in doses of 0.5-4 mg/day over 8 weeks of treatment. The efficacy of other second generation antipsychotics and mood stabilizers on anxiety in patients with bipolar disorder and a co-occuring anxiety disorder should be investigated in double-blind, placebo-controlled studies.

Abstract

The clinician-rated, 16-item Quick Inventory of Depressive Symptomatology (QIDS-C16) has been extensively evaluated in patients with major depressive disorder (MDD). This report assesses the psychometric properties of the QIDS-C16 in outpatients with bipolar disorder (BD, N = 405) and MDD (N = 547) and in bipolar patients in the depressed phase only (BD-D) (N = 99) enrolled in the Texas Medication Algorithm Project (TMAP) using classical test theory (CTT) and the Samejima graded item response theory (IRT) model. Values of coefficient alpha were very similar in BD, MDD, and BD-D groups at baseline (alpha = 0.80-0.81) and at exit (alpha = 0.82-0.85). The QIDS-C16 was unidimensional for all three groups. MDD and BD-D patients (n = 99) had comparable symptom levels. The BD-D patients (n = 99) had the most, and bipolar patients in the manic phase had the least depressive symptoms at baseline. IRT analyses indicated that the QIDS-C16 was most sensitive to the measurement of depression for both MDD patients and for BD-D patients in the average range. The QIDS-C16 is suitable for use with patients with BD and can be used as an outcome measure in trials enrolling both BD and MDD patients.

Abstract

There is growing interest in the utility of nonpharmacologic treatments for mood symptoms, including mood elevation and depression associated with bipolar disorders. The purpose of this research was to provide preliminary data on the safety, effectiveness, and acceptability of adjunctive acupuncture in the acute treatment of hypomania and depression associated with bipolar disorder.Two randomized trials were conducted to assess the benefits of adjunctive acupuncture for symptoms of depression and hypomania in patients with bipolar disorder (DSM-IV criteria). For 20 patients experiencing symptoms of hypomania, targeted acupuncture (points specific to symptoms) was compared to acupuncture points off the acupuncture meridian over 12 weeks (from May 2000 through May 2003). For patients experiencing symptoms of depression (n = 26), targeted acupuncture was compared to acupuncture for nonpsychiatric health concerns over 8 weeks (from November 2001 through May 2003). Preexisting psychotropic medications were maintained at stable doses throughout study participation.Regardless of acupuncture assignment or symptom pattern at entry, all patients experienced improvement over the course of study participation. There was evidence that acupuncture treatment did target the symptom dimension of interest (mood elevation in Study I, depression in Study II). There were few negative side effects and no attrition directly associated with adjunctive acupuncture.Novel methodologies are needed to assess the utility of acupuncture as adjunctive treatment of mood episodes associated with bipolar disorder. We observed similar benefits associated with "placebo" acupuncture experiences and active treatment. Further studies are warranted. TRIAL REGISTRATION (STUDY II): (ClinicalTrials.gov) Identifier: NCT00071669.

Maintenance Treatment for Patients With Bipolar I Disorder: Results From a North American Study of Quetiapine in Combination With Lithium or Divalproex (Trial 127)46th Annual Meeting of the American-College-of-NeuropsychopharmacologySuppes, T., Vieta, E., Liu, S., Brecher, M., Paulsson, B.AMER PSYCHIATRIC PUBLISHING, INC.2009: 476?88

Abstract

The authors evaluated the efficacy and safety of quetiapine plus lithium or divalproex in the prevention of recurrent mood events in patients with stabilized bipolar I disorder.A total of 1,953 patients received open-label quetiapine (400-800 mg/day in flexible, divided doses) with either lithium or divalproex (target serum concentrations 0.5-1.2 meq/liter and 50-125 microg/ml, respectively) for up to 36 weeks. After at least 12 weeks of clinical stability, 628 patients were randomly assigned to double-blind treatment with quetiapine or placebo, in combination with lithium or divalproex, for up to 104 weeks. The primary efficacy measure was time to recurrence of any mood event (mania, depression, or a mixed episode).Fewer patients in the quetiapine group experienced a mood event compared with the placebo group (20.3% versus 52.1%). The hazard ratio for time to recurrence of a mood event was 0.32. Hazard ratios were similar for mania and depression events (0.30 and 0.33, respectively). Sedation, weight increase, and hypothyroidism occurred more frequently in the quetiapine group, as did discontinuations due to adverse events. The incidence and incidence density of a single emergent blood glucose value > or =126 mg/dl were higher in the quetiapine group (12.6% versus 5.4%; 18.44 versus 9.56 patients per 100 patient-years). Adverse events were generally consistent with the known tolerability profile of quetiapine.In patients stabilized on quetiapine plus lithium or divalproex, continued treatment was associated with a significant risk reduction in the time to recurrence of any mood event compared with placebo and lithium or divalproex.

Abstract

To assess long-term outcome in bipolar disorder, subjects were prospectively followed after receiving acute treatment for bipolar depression.Eighty-three outpatients with DSM-IV bipolar depression who were enrolled between March 1996 and November 2002 and were treated in a 10-week acute double-blind antidepressant treatment trial agreed to participate in a 1-year double-blind continuation of their medication. In the acute antidepressant treatment trial, subjects were treated with a mood stabilizer plus 1 of 3 randomly assigned antidepressants. Sixty-one subjects had attained an acute positive antidepressant response (50% improvement on the Inventory for Depressive Symptomatology [IDS] or 2-point improvement on the Clinical Global Impression for Bipolar Disorder [CGI-BP]) and 22 subjects achieved only acute partial improvement at the end of the 10-week acute trial. In the blinded continuation phase immediately following the acute trial, subjects continued on the same medications and were rated monthly for up to 1 year using the IDS, CGI-BP, and the Young Mania Rating scale.At study endpoint, 42 (69%) of the 61 acute positive responders maintained positive response and 32 (53%) achieved remission. Compared to the acute positive responders, 6 (27%) of the 22 acute partial responders had achieved positive treatment response at study endpoint (p < .001). Eight acute positive responders (13%) and 5 acute partial responders (22%) developed mania.Patients who achieve a positive acute antidepressant response to 10 weeks of antidepressant treatment adjunctive to a mood stabilizer will probably maintain response with the same continued treatment. Patients who achieve only a partial acute antidepressant response are less likely to further improve when the same treatment is sustained. The switch rate into mania for patients being treated with an antidepressant adjunctive to a mood stabilizer is not higher than the reported rate for patients on mood stabilizer monotherapy.

Abstract

Treatment-emergent mania can have substantial negative impact on overall mood and psychosocial stability in patients receiving treatment for bipolar depression. This study examined the correlates associated with treatment-emergent mania in patients receiving adjunctive antidepressant treatment for bipolar depression.A total of 176 adult outpatients with bipolar disorder in a 10-week trial of adjunctive antidepressant treatment for depression were categorized into three groups based on the Clinical Global Impression Scale for Bipolar Disorder: those who responded to antidepressant treatment (N=85), those who did not respond to antidepressant treatment (N=45), and those who had treatment-emergent mania or hypomania (N=46). Symptom severity was measured with the Inventory of Depressive Symptomatology and the Young Mania Rating Scale (YMRS) at baseline and bimonthly intervals. Factor analysis was used to examine correlates of treatment-emergent mania.Baseline YMRS scores were significantly different between groups. Otherwise, there were no significant between-group differences in demographic or clinical characteristics. Factor analysis showed that a subset of the YMRS items predicted treatment-emergent mania in this sample: increased motor activity, speech, and language-thought disorder.These data suggest that minimal manic symptoms at baseline coexisting with otherwise full syndromal bipolar depression are associated with antidepressant treatment-emergent mania or hypomania. A careful examination of motor activation, pressured speech, and racing thoughts is warranted before starting antidepressant treatment in bipolar depression.

Abstract

Treatment studies are lacking for patients with bipolar II disorder (BDII). The objective of this study was to compare lamotrigine (LTG) and lithium (Li) monotherapy for the treatment of BDII depression.Patients with BDII acute depression were randomized to open-label monotherapy with LTG or Li, and evaluated by trained raters blinded to treatment. Patients were titrated to 200 mg/day of LTG over 8 weeks or at least 900 mg/day of Li over 2 weeks (serum level 0.6-1.2 mEq/L), and seen biweekly for 16 weeks. The primary outcome variable was change in the Hamilton Depression Rating Scale 17-item (Ham-D(17)), evaluated using mixed effects random regression.Both groups showed significant improvement from baseline to endpoint on the Ham-D(17) (p<0.0001), with no between group differences (p=0.95). Seventy-two percent of the population was rapid cycling by DSM-IV criteria. No differences in response were noted between rapid cyclers and non-rapid cyclers. Early termination for any cause was 42%. The Li group reported significantly more side effects, although drop-out due to side effects did not differ between groups.This study was limited by an open treatment design, a lack of placebo arm, and uneven treatment groups.Lamotrigine and lithium were effective monotherapy for BDII depression, with comparable response and remission rates. Naturalistic design and lack of placebo limit conclusions, though patient history indicated long standing depression unlikely to be alleviated by time. Patients who received Li reported more side effects, but this did not appear to impact drop-out rates.

Abstract

This study examined the efficacy and safety of quetiapine in combination with lithium or divalproex compared with placebo with lithium or divalproex in the prevention of recurrent mood events in bipolar I patients, most recent episode mania, depression, or mixed.Patients received open-label quetiapine (400-800 mg/day; flexible, divided doses) with lithium or divalproex (target serum concentrations 0.5-1.2 mEq/L and 50-125 microg/mL, respectively) for up to 36 weeks to achieve at least 12 weeks of clinical stability. Patients were subsequently randomized to double-blind treatment with quetiapine (400-800 mg/day) plus lithium/divalproex or placebo plus lithium/divalproex for up to 104 weeks. The primary endpoint was time to recurrence of any mood event.Treatment with quetiapine in combination with lithium/divalproex significantly increased the time to recurrence of any mood event compared with placebo plus lithium/divalproex. The proportion of patients having a mood event was markedly lower in the quetiapine than in the placebo group (18.5% versus 49.0%). The hazard ratio for time to recurrence of a mood event was 0.28 (P<0.001), a mania event 0.30 (P<0.001), and a depression event 0.26 (P<0.001) corresponding to risk reductions of 72%, 70%, and 74%, respectively. During the randomization phase, the most common adverse events occurring in > or =5% in the quetiapine group were somnolence, nasopharyngitis, and headache. Insomnia was more common in the placebo group. During the randomization phase, there was an increase in weight of 0.5 kg in the quetiapine group and a reduction of 1.9 kg in the placebo group. The incidence and incidence density of a single emergent fasting blood glucose value> or =126 mg/dL was higher with quetiapine than with placebo (9.3% versus 4.1%; 17.6 versus 9.5 patients per 100 patient-years).This was an enriched sample of patients with bipolar I disorder responding to treatment with quetiapine plus lithium/divalproex.Maintenance treatment with quetiapine in combination with lithium/divalproex significantly increased time to recurrence of any event (mania, depression, or mixed) irrespective of the polarity of the index episode compared with placebo with lithium/divalproex. Long-term treatment with quetiapine was generally well-tolerated. Quetiapine with lithium/divalproex can provide an effective long-term treatment option for bipolar I disorder to prevent recurrences not only of mania but also depression.

Abstract

To investigate the efficacy and tolerability of quetiapine monotherapy for the treatment of major depressive episodes in patients with bipolar I disorder, as a post hoc analysis of data from 2 large studies, the BipOLar DEpRession (BOLDER) I and II studies, which investigated the overall efficacy of quetiapine in both bipolar I and II disorder.A combined cohort of patients with depressive episodes in bipolar I disorder (DSM-IV criteria) (N = 694) from 2 nearly identical double-blind, randomized, placebo-controlled studies that each randomly assigned patients with bipolar I and II disorder to 8 weeks of treatment with quetiapine 300 or 600 mg/day or placebo was analyzed. The primary efficacy measure was change from baseline to end of treatment (week 8) in the Montgomery-Asberg Depression Rating Scale (MADRS) total scores.In the combined cohort of patients with depressive episodes in bipolar I disorder from 2 studies, there were significantly greater clinical improvements in mean MADRS total scores among patients who received quetiapine compared with placebo from baseline to week 1 and through week 8 (at week 8: quetiapine 300 mg/day = -19.4; 600 mg/day = -19.6; placebo = -12.6; p < .001 for each dose), providing effect sizes of 0.78 and 0.80, respectively. Changes in MADRS were unrelated to reports of sedation and somnolence. The most common adverse events (AEs) with quetiapine were dry mouth, somnolence, sedation, dizziness, and constipation. Rates of withdrawal because of these AEs were relatively low.Quetiapine monotherapy (300 and 600 mg/day) is more effective than placebo and generally well tolerated for the treatment of depressive episodes in patients with bipolar I disorder.

Abstract

An online survey of European psychiatrists assessed awareness of the metabolic syndrome and its influence on the management of bipolar disorder.Psychiatrists in the United Kingdom, France, Germany, Spain, and Italy were surveyed from April to June 2006. Eligibility criteria w ere 4-30 years in practice, >or=50% of time in direct patient care, had seen >or=10 bipolar patients in the preceding month. Aggregate data were weighted to represent the practicing physician population per country.Of 718 respondents, 56% had diagnosed metabolic syndrome. Respondents reported that metabolic syndrome prevalence was higher in bipolar patients (25%) than in the general population (20%). Seventy-two percent felt that metabolic syndrome poses significant health risks, warranting monitoring/treatment, and were most concerned with the bipolar medication adverse effects of weight gain, cognitive impairment, and glucose intolerance. Survey respondents recognized clear differences among psychotropic agents in the propensity to induce metabolic adverse effects. Sixty-five percent of respondents indicated that they had made interviewing and monitoring changes in the past three years as a result of metabolic concerns.European psychiatrists view metabolic syndrome as highly prevalent in the general population and in bipolar patients; two-thirds have changed their management of bipolar patients because of metabolic health concerns.

Abstract

This analysis was designed to assess the efficacy and safety of aripiprazole compared with placebo in subpopulations of patients with acute manic or mixed episodes of bipolar I disorder.Acutely manic patients experiencing DSM-IV manic/mixed episodes of bipolar I disorder were pooled from two randomized, three-week, flexible-dose, double-blind, placebo-controlled trials (N=516) and stratified by disease severity (Young Mania Rating Scale, YMRS), episode type, presence or absence of psychotic features, episode frequency, age, gender, and baseline severity of depressive symptoms. Safety and treatment-emergent adverse-event analyses were also performed.Aripiprazole significantly reduced mean YMRS total scores at end point compared with placebo in patients with more severe or less severe illness, with mixed or manic episodes, with or without psychotic features, or with a history of rapid or non-rapid cycling (p<0.01 for each subpopulation); in men and women (p=0.001 for both); in patients in the 18-40 and 41-55 year age groups (por=5% of patients aged 18-40 years receiving aripiprazole were similar to those reported for the overall population.This post hoc analysis utilized pooled data from two short-term studies.Efficacy of the second-generation antipsychotic aripiprazole was noted across a broad range of subpopulations often associated with treatment resistance in patients experiencing manic or mixed episodes of bipolar I disorder.

Abstract

Evidence suggests gender differences may exist in bipolar disorder, and a review of the literature shows that more women than men may experience rapid-cycling bipolar disorder. The issues contributing to these gender differences are unknown; a number of case reports have indicated the possibility of mood changes secondary to hormonal influences during the menstrual cycle. We sought to examine the relationship between bipolar disorder and menstrual cycle-related mood changes. To our knowledge, this is one of the largest samples in the literature addressing this issue.Outpatient women with bipolar disorder I, bipolar disorder II, and not otherwise specified (NOS), between the ages of 18 and 45, were evaluated. The National Institute of Mental Health Life Chart Method-p (NIMH-LCM-p) was used for daily mood ratings of depression and mania. Repeated measures of ANOVA and t tests were conducted separately for depressive and for manic symptom scores.One hundred nineteen women met the age criterion, and only 41 women met the rest of the inclusion criteria. In this sample of 41 women, there was no significant relationship between phases of the menstrual cycle (early and late follicular and early and late luteal phases) and changes in depression or mania. In an exploratory examination, 8 of 41 women showed a numerically higher mean depression score in the luteal phase than in the follicular phase; 5 of 41 women showed a numerically higher mean mania score in the luteal phase than in the follicular phase of the menstrual cycle.Different phases of the menstrual cycle were unrelated to depression and mania in a heterogeneous group of women with bipolar disorder. Prospective studies are needed to identify a vulnerable subpopulation in a homogeneous clinical sample.

Abstract

The relative incidence of childhood-onset bipolar illness in the USA compared with that in Europe is controversial. We examined this issue in more than 500 out-patients (average age 42 years) with bipolar illness who reported age at onset of first episode, family history, and childhood physical or sexual abuse. Childhood or adolescent onset of bipolar illness was reported by 61% of those in the US cohort but by only 30% of those in The Netherlands or Germany. In the USA there was also twice the incidence of childhood adversity and genetic/familial risk for affective disorder. The findings deserve replication and further exploration.

Abstract

Vagus nerve stimulation (VNS) appears to be an effective treatment option for patients with treatment-resistant unipolar and bipolar depression. The aim of the present study was to investigate the efficacy of VNS in a group of patients with treatment-resistant rapid-cycling bipolar disorder (RCBD) who were excluded from previous trials.Nine outpatients with a DSM-IV-TR diagnosis of treatment-resistant RCBD were treated for 40 weeks with open-label VNS. The first patient was enrolled in June 2001, and the last patient completed the study in July 2005. Patients recorded their depression and mania mood symptoms on a daily basis throughout the study using the National Institute of Mental Health prospective life charting methodology and daily mood ratings. Patients were assessed every 2 weeks during the 2-month baseline period before device activation, every 2 weeks for the remaining 40 weeks of the study, and at the end of the study with the 24-item Hamilton Rating Scale for Depression (HAM-D-24), the 10-item Montgomery-Asberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), the Clinical Global Impressions (CGI) scale, the Global Assessment of Functioning (GAF) scale, and the 30-item Inventory of Depressive Symptomatology Self-Report (IDS-SR-30). Any adverse events or device complications were also recorded at each visit. The prospective life charts were analyzed by calculating the area under the curve. Statistical analysis was performed with a mixed-model repeated-measures regression analysis for repeated measures of the various rating scales. Significant p values were < or = .05.Over the 12-month study period, VNS was associated with a 38.1% mean improvement in overall illness as compared to baseline (p = .012), as well as significant reductions in symptoms as measured by the HAM-D-24 (p = .043), MADRS (p = .003), CGI (p = .013), and GAF (p < .001) rating scales. Common adverse events were voice alteration during stimulation and hoarseness.These data suggest that VNS may be an efficacious and well-tolerated treatment option for patients with treatment-resistant RCBD. Currently, no comparison is available in the literature. Larger randomized trials are needed to verify these findings.

Abstract

As a commitment to the International Society for Bipolar Disorders (ISBD), a Task Force was developed to investigate the diagnostic value of bipolar II disorder.Task Force members worked jointly reviewing all relevant literature (original articles, reviews, letters, book chapters and congress presentations) that included 'bipolar II disorder' and/or 'hypomania' as key words.Bipolar II disorder appears to be a reasonably valid and reliable diagnostic category yet often underdiagnosed or misdiagnosed as unipolar disorder or personality disorder. Moreover, it is officially recognized as a mental disorder in DSM-IV-TR but not in ICD-10, and many clinicians still regard it as a milder form of manic-depressive illness, despite data supporting high morbidity and mortality rates. In fact, bipolar II may be the most prevalent bipolar phenotype, although current diagnostic boundaries are seen as quite restrictive concerning the required duration for hypomania (4 days), the exclusion of hypomanic episodes potentially triggered by antidepressants and other substances, and the negligence of hypomanic mixed states. The course of bipolar II disorder is characterized by depressive predominant polarity, and its treatment is still controversial and poorly evidence-based.Bipolar II disorder is supported as a distinct category within mood disorders, but the definition and boundaries deserve a greater clarification in the DSM-V and ICD-11.

Abstract

Fluctuations in mood are quintessential features of bipolar disorder; however, previous studies have seldom examined the extent to which pharmacotherapies for bipolar disorder may reduce or ameliorate daily or weekly mood variability. The anticonvulsant lamotrigine has demonstrated efficacy for relapse prevention in bipolar disorder, but its possible mood-stabilizing properties on a day-to-day or week-to-week basis have not previously been investigated.Weekly mood shifts were examined over 26 weeks using patients' self-reported prospective Life Chart Method (LCM) data obtained as part of a previously reported randomized relapse prevention comparison of lamotrigine monotherapy or placebo in 182 bipolar patients with DSM-IV rapid cycling. Generalized estimating equation (GEE) analyses were used to compare treatment arms for subjects who achieved euthymia across weeks.After adjusting for potential confounding factors, a final GEE model revealed that subjects taking lamotrigine were 1.8 times more likely than those taking placebo to achieve euthymia, as measured by LCM, at least once per week over 6 months (95% confidence interval [CI] = 1.03-3.13). Subjects taking lamotrigine had an increase of .69 more days per week euthymic as compared with those taking placebo (p = .014).Achievement of euthymia across weeks represents a novel paradigm shift in gauging the mood-stabilizing properties of a psychotropic agent. The present findings demonstrate the utility of the prospective Life Chart Method for assessing longitudinal mood stability during randomized clinical trials for bipolar disorder. The results lend support to the potential mood-stabilizing properties of lamotrigine monotherapy for bipolar disorder.

Abstract

To investigate the efficacy and tolerability of quetiapine monotherapy for depressive episodes in patients with bipolar II disorder.A post-hoc evaluation was conducted in 351 patients with bipolar II depression combined from two similarly designed double-blind, randomized, placebo-controlled, 8-week studies of quetiapine (300 or 600 mg/day) that included patients with bipolar I or II disorder (DSM-IV) exhibiting moderate to severe depression. The primary endpoint was change from baseline to week 8 in MADRS total score. Secondary endpoints included HAM-D, HAM-A, and CGI.In patients with bipolar II disorder, improvement in mean MADRS total score from baseline was significantly greater with quetiapine 300 (n = 107) and 600 mg/day (n = 106) from the first assessment (week 1) through week 8 compared with placebo (n = 108). The mean change from baseline at week 8 for quetiapine 300 and 600 mg/day versus placebo was -17.1 and -17.9 versus -13.3 (P = 0.005 and P = 0.001 versus placebo), respectively. Change in HAM-D, HAM-A, and CGI were also significantly greater for quetiapine groups versus placebo. Common adverse events in the quetiapine groups included dry mouth, sedation, and somnolence.Quetiapine demonstrated significant efficacy as monotherapy, compared with placebo, for the treatment of acute depressive episodes in bipolar II disorder.

Abstract

Hyperprolactinemia is increasingly studied as a frequent and potentially important consequence of antipsychotic medication treatment. Some individuals presenting with hyperprolactinemia remain asymptomatic, but others may exhibit a wide range of clinical symptoms resulting from either the direct effects of prolactin on body tissues (galactorrhea, gynecomastia) or endocrine-related secondary effects (sexual and reproductive dysfunction in the short term, and possibly the risk of tumorigenesis and osteoporosis in the longer term). Short-term side effects may negatively impact medication compliance, and long-term effects have the potential for serious health consequences. Antipsychotic medications have differing propensities to cause prolactin elevation. The first-generation antipsychotics, as well as the second-generation antipsychotic risperidone and its active metabolite paliperidone, have been shown to cause marked and sustained elevations in prolactin levels, whereas others of the second-generation antipsychotics appear to have little or no effect on prolactin levels or may decrease prolactin. A comprehensive overview of antipsychotics and hyperprolactinemia is presented together with a review of emerging evidence about the short- and long-term health risks of hyperprolactinemia.

Abstract

Continuation treatment for bipolar disorder often consists of a mood stabilizer and a second-generation antipsychotic. Quetiapine has been shown to be an effective treatment for acute mania and acute bipolar depression, but there are limited data for its use in continuation treatment. This study examined the effectiveness of open-label adjunctive quetiapine therapy for continuation treatment in patients with bipolar disorder. Prospectively collected life chart data from 63 outpatients with bipolar disorders, most recent episodes depressed, manic, or cycling, who received adjunctive quetiapine therapy as part of standard acute treatment were analyzed. Patients had 4 or more weeks of prequetiapine baseline data and at least 2 weeks of quetiapine treatment with no other medication changes. Patients were grouped by baseline symptoms; depression only, mania only, or both mania and depression (cycling group). Owing to small mania and well groups (n=4), differences between depression and cycling groups were examined and mania and well groups excluded. Fifty-five patients were included in the analyses. The primary outcome measure was change in mood severity from baseline to change in treatment regimen, as measured by the NIMH Life Charting Method. Patients received adjunctive quetiapine for a mean of 122 (SD=149) days. Both groups showed significant improvement in depression ratings and time spent depressed by week 10. Both groups showed significant improvement in overall mood. No between-group differences in improvement were found. Adjunctive quetiapine may be useful as continuation treatment in bipolar populations with both pure depressive and cycling symptoms. Further controlled studies are warranted.

Abstract

To assess the proportion of time spent in mania, depression and euthymia in a large cohort of bipolar subjects studied longitudinally, and to investigate depression/mania ratios in patients with bipolar I versus bipolar II disorder.Clinician-adjusted self-ratings of mood were completed daily for one year for naturalistically treated outpatients with bipolar I (n = 405) or bipolar II (n = 102) disorder. Ratings were analyzed for mean time spent euthymic, depressed, manic, hypomanic, and cycling, and the percentages of time spent ill were compared between the two groups.Percentages of time spent ill for bipolar I versus II patients were: euthymia 47.7% versus 50.2%; depression 36.0% versus 37.0%; hypomania 11.5% versus 9.8%; mania 1.0% versus 0.2%; and cycling 3.7% versus 2.8%. The depression/mania ratio was 2.9 in the bipolar I and 3.8 in bipolar II sub-groups.Depression represents the predominant abnormal mood state for treated outpatients with bipolar I and II disorder. In contrast to other studies, we found that depression/mania ratios were of a similar magnitude, suggesting the same tendency towards mood instability in both sub-groups.

Abstract

Increasing evidence indicates that some second-generation antipsychotics are efficacious in bipolar depression, but there are few data on this illness for the novel agent aripiprazole.Aripiprazole response was prospectively assessed for 8 weeks with the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression Scale Modified for Bipolar Illness (CGI-BP), and the Young Mania Rating Scale (YMRS) in 31 bipolar patients with acute depression inadequately responsive to 1 mood stabilizer. Side effects and body weight were also evaluated. Outcome measures were analyzed with repeated measures ANOVAs.Patients showed a significant decrease in mean MADRS total and CGI-BP-Depression Severity scores, but only 14 (45%) completed the 8-week trial. Thirteen (42%) patients met criteria for response (> or =50% reduction in MADRS total score), 11 (35%) patients met criteria for remission (final MADRS total score < or =12), and 9 (29%) patients discontinued aripiprazole for side effects, most commonly akathisia (N=4). As a group, patients showed statistically insignificant weight gain (0.8+/-2.5 kg) over the 8-week trial.Aripiprazole was associated with beneficial effects on mood in some patients with bipolar depression, but also had a high discontinuation rate, primarily due to side effects. Double-blind, placebo-controlled studies are necessary to determine aripiprazole's efficacy, tolerability, and safety in bipolar depression.

Abstract

This study was undertaken to evaluate the prevalence rate of anxiety comorbidity in bipolar subjects with and without alcohol use disorders (AUD).Bipolar men and women who entered the Stanley Foundation Bipolar Network (SFBN) underwent a Structured Clinical Interview for DSM-IV (SCID-IV) and were divided into those subjects meeting current or lifetime criteria for an alcohol use disorder (AUD=213) vs. those subjects who did not (non-AUD=137). Lifetime rates of comorbid anxiety disorder were evaluated between groups.Of 350 subjects, 163 (46.5%) met criteria for an anxiety disorder. Panic disorder and OCD were the most common anxiety disorders in the AUD and non-AUD groups. OCD and specific phobia were significantly less prevalent in BP I patients with AUD compared to those without. Bipolar women with AUD had a significantly higher rate of PTSD than those without.These data highlight the added liability of anxiety comorbidity in BP disorder. Specifically, the greater amount of PTSD and lesser amount of OCD in bipolar women with alcohol comorbidity may have important diagnostic and treatment implications beyond dual diagnosis. Further study in comorbidity patterns is encouraged to not only better understand illness burden, but to maximize pattern-specific treatment outcomes.

Abstract

Modafinil is approved by the U.S. Food and Drug Administration for improving wakefulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift-work sleep disorder. This study was conducted to evaluate the efficacy and safety of adjunctive modafinil in bipolar depression, which is often characterized by excessive sleepiness and fatigue.Eighty-five patients with bipolar depression that was inadequately responsive to a mood stabilizer with or without concomitant antidepressant therapy were randomly assigned to receive adjunctive modafinil (N=41) or placebo (N=44) for 6 weeks. The primary outcome measure was baseline-to-endpoint change in score on the Inventory of Depressive Symptoms--Clinician Rated (IDS).The baseline-to-endpoint change in IDS score was significantly greater in the modafinil group (mean dose, 177 mg/day) compared with the placebo group. Improvement in depressive symptoms was significantly greater in the modafinil group by week 2, and this greater improvement was maintained at weeks 4, 5, and 6. Both the response and remission rates were significantly higher in the modafinil group (44% and 39%) compared with the placebo group (23% and 18%). During the 6-week study period, there was no difference between groups in treatment-emergent hypomania or mania (six patients in the modafinil group and five in the placebo group) or hospitalization for mania (one in each group).These data suggest that adjunctive modafinil at doses of 100-200 mg a day may improve depressive symptoms in patients with bipolar disorder.

Abstract

In this paper, we discuss the conceptual background for including a dimensional component to the DSM V diagnoses for psychoses. We review the evidence for a continuous distribution of psychosis like symptoms in the general population and summarise the research validating the clinical usefulness of psychopathological dimensions. We conclude that diagnostic models using both categorical and dimensional representations of psychosis have better predictive validity than either model independently. Dimensions do not appear to be diagnosis specific so a flexible scoring of dimensions across all psychotic and major affective disorders may be potentially more informative than a system where categorical diagnoses are kept artificially dimension-specific.

Abstract

Patients with bipolar disorder (BD) have an increased risk of obesity as well as psychotropic-associated weight gain. The objective of this study was to compare sibutramine and topiramate as adjunctive treatments for psychotropic-associated weight gain in overweight or obese outpatients with BD.In this 24-week, open-label, flexible-dose, comparison trial, 46 outpatients with bipolar disorders who had a body mass index (BMI) > or =30 kg/m(2), or > or =27 kg/m(2) with obesity-related comorbidities, and psychotropic-associated weight gain were randomly assigned to receive sibutramine (n = 18; 5-15 mg/day) or topiramate (n = 28; 25-600 mg/day). The primary outcome measure was weight loss. Secondary measures included changes in BMI, percent body weight loss, and mood symptoms.Patients randomized either to sibutramine or topiramate lost comparable amounts of weight (4.1 +/- 5.7 and 2.8 +/- 3.5 kg, respectively) and displayed similar rates of weight loss (0.85 and 0.82 kg/week, respectively). However, only four (22%) patients receiving sibutramine and six (21%) patients receiving topiramate completed the 24-week trial. In addition, the attrition patterns for the two drugs were different, with patients discontinuing topiramate doing so early in treatment and patients discontinuing sibutramine doing so throughout treatment. Also, higher ratings of manic and depressive symptoms significantly increased risk for early topiramate discontinuation compared to that for sibutramine.Adjunctive sibutramine and topiramate may have comparable weight loss effects in overweight or obese bipolar patients with psychotropic-associated weight gain, but are each associated with similarly high discontinuation rates. In addition, they may have different attrition profiles. Compared to sibutramine, discontinuation of topiramate may be more likely to occur early in treatment and may be more dependent upon manic and depressive symptoms.

Abstract

To compare the efficacy and tolerability of tranylcypromine vs. lamotrigine in bipolar depression not responding to conventional antidepressants.Bipolar depressed patients received open randomized treatment with tranylcypromine or lamotrigine as add-on to a mood stabilizer during 10 weeks. In a second treatment phase, non-responding patients could receive the opposite drug. Outcome criteria were response (measured with CGI-BP and IDS-C), switch into mania, and completion of the study.Only 20 of 70 planned patients were randomized, due to problems with recruitment, and 19 patients received any medication. During the first treatment phase 5/8 patients (62.5%) responded to tranylcypromine without switch into mania, compared with 4/11 patients (36.4%) on lamotrigine with two switches (statistically not significant). Over both treatment phases, 8/10 patients (80%) receiving tranylcypromine completed the study vs. 5/13 (38.5%) on lamotrigine (likelihood 0.02).There still appears to be a role for tranylcypromine in the treatment of refractory bipolar depression. Larger controlled studies are demanded.

Abstract

We examined age of onset of bipolar disorder as a potential course-of-illness modifier with the hypothesis that early onset will engender more severe illness.A total of 480 carefully diagnosed adult outpatients with bipolar disorder (mean age, 42.5 +/- 11.6 years) were retrospectively rated for age of illness onset, time to first pharmacotherapy, and course of illness. Clinicians prospectively rated daily mood fluctuations over 1 year.Of the 480 patients, 14% experienced onset in childhood (12 years or younger); 36% in adolescence (13 to 18 years); 32% in early adulthood (19 to 29 years); and 19% in late adulthood (after 30 years). Childhood-onset bipolar illness was associated with long delays to first treatment, averaging more than 16 years. The patients with childhood or adolescent onset reported more episodes, more comorbidities, and rapid cycling retrospectively; prospectively, they demonstrated more severe mania, depression, and fewer days well.This study demonstrates that childhood onset of bipolar disorder is common and is associated with long delays to first treatment. Physicians and clinicians should be alert to a possible bipolar diagnosis in children in hopes of shortening the time to initiating treatment and perhaps ameliorating the otherwise adverse course of illness.

Abstract

Oxcarbazepine was compared to divalproex to assess clinical effectiveness of a proven agent, divalproex, against a newer, less studied agent, oxcarbazepine, in the treatment of hypomania.Thirty patients with bipolar disorder, currently hypomanic, were randomized to receive oxcarbazepine or divalproex as add-on or monotherapy for 8 weeks. A rater blind to treatment assignment performed all symptom ratings. Hypomania and depression were rated using the Young Mania Rating Scale (YMRS) and the Inventory of Depressive Symptoms-Clinician Version (IDS-C). Random regression models were used to assess clinical symptom scores.There were no significant differences of YMRS or IDS-C scores between groups. Mean YMRS scores at baseline were 22.07+/-5.86 and 20.53+/-6.02 for the oxcarbazepine and the divalproex groups, respectively. Mean percent reduction from baseline to week 8 for the YMRS was 63.8% and 79.0% for oxcarbazepine and divalproex groups, respectively. Mean percent reduction from baseline to week 8 for the IDS-C was 48.7% versus 19.7% for oxcarbazepine and divalproex groups, respectively. Significant antimanic efficacy was noted for each medication. Both medications were generally well tolerated.In this pilot study, oxcarbazepine was as effective as divalproex in the treatment of hypomania. Further controlled trials are warranted.

Abstract

An online survey was conducted to assess psychiatrists' familiarity with the metabolic syndrome and its components in patients with bipolar disorder, and characterize their perspectives and practices regarding its impact on patient management.Participants were US psychiatrists from a random sample of those in the AMA database. Qualified respondents practiced 4-30 years, spent > or = 50% of their time in direct patient care, and treated > or = 25 bipolar patients in the last month. Results were collected and tabulated by Harris Interactive from Nov-Dec 2005.Five hundred psychiatrists qualified and completed the survey, and 50 respondents also participated in follow-up interviews. Most respondents (94%) viewed metabolic syndrome as a significant health risk requiring monitoring and treatment. While 76% have diagnosed it, only 28% correctly identified the five NCEP diagnostic criteria. Medication adverse effects of greatest concern were weight gain, glucose intolerance, and dyslipidemia. During treatment, 78% of respondents reported monitoring weight, 69% glucose, 61% lipids, and 52% blood pressure. Most respondents (92%) reported referring patients to specialists or primary care for metabolic abnormalities. Changes in metabolic profile were reported to prompt many psychiatrists (85%) to stop or switch bipolar medications, especially those who treat a large number of bipolar patients (89%). The follow-up interviews supported a change in practice patterns over the last 5 years.Nearly all respondents have metabolic concerns with medical therapies used to treat bipolar disorder. Many now routinely monitor weight and other metabolic parameters. Most have referred patients for medical management and adjusted bipolar therapies due to metabolic abnormalities.

Abstract

In the Systematic Treatment Enhancement Program for Bipolar Disorder, we showed that valproate is associated with new-onset menstrual-cycle irregularities and hyperandrogenism in 10.5% of 86 women. We now determine whether polycystic ovarian syndrome (PCOS) features reverse on valproate discontinutation.Women with valproate-associated PCOS and those at risk for PCOS (valproate use < or =6 months) were re-evaluated for PCOS.Follow-up (mean 17 months) assessments were completed in 14 women (5 with treatment-emergent PCOS, 9 on valproate < or =6-month). Of seven women who developed valproate-associated PCOS, PCOS reproductive features remitted in three of four discontinuing valproate and persisted in all 3 continuing valproate. Menstrual-cycle irregularities improved among valproate-discontinuers whose PCOS features remitted (p = 0.01). There was a trend toward lower serum testosterone (p = 0.06). Body-weight and polycystic ovarian morphology did not change.In the first longitudinal bipolar-disorder study of valproate-associated PCOS, most valproate-discontinuers had improved reproductive features of PCOS despite static body-weight.

Abstract

In this article, we highlight recent Bipolar Collaborative Network data. We found that childhood-onset bipolar illness is common, often goes untreated for more than a decade, and carries a poor prognosis. During randomized studies of adjunctive medications in depression: 1) Venlafaxine showed higher switch rates than bupropion or sertraline; 2) Tranylcypromine was as well tolerated as lamotrigine; and 3) Modafinil was more effective than placebo. Finally, in treatment of overweight and obesity, topiramate and sibutramine showed equal efficacy but poor tolerability, and zonisamide data showed that it may be useful for mood and weight loss.

Abstract

The results of pilot trials suggest that omega-3 fatty acids may have efficacy in the treatment of mood symptoms in bipolar disorder.We conducted a 4-month, randomized, placebo-controlled, adjunctive trial of ethyl-eicosapentanoate (EPA) 6 g/day in the treatment of bipolar depression and rapid cycling bipolar disorder. Subjects were receiving mood-stabilizing medications at therapeutic doses or plasma concentrations. The measures of efficacy were early study discontinuation, changes from baseline in depressive symptoms (Inventory for Depressive Symptomology total score) and in manic symptoms (Young Mania Rating Scale total score), and manic exacerbations ("switches"). We also measured side effects and bleeding time, a biomarker of drug action.Overall, there were no significant differences on any outcome measure between the EPA and placebo groups.This study did not find overall evidence of efficacy for adjunctive treatment with EPA 6 g/day in outpatients with bipolar depression or rapid cycling bipolar disorder.

Abstract

Subsyndromal symptoms in bipolar disorder can cause significant functional impairment and are associated with relapse.In this post hoc analysis from 2 randomized, double-blind, 18-month, placebo-controlled maintenance trials for bipolar I disorder (both trials were conducted between August 1997 and August 2001 and used DSM-IV criteria), the incidence, time course, and impact of pharmacotherapy on subsyndromal symptoms were examined.Subsyndromal symptoms occurred in approximately 25% of all visits. Compared with placebo (54.8%), a significantly higher mean percentage of visits in remission were observed with lamotrigine treatment (63.0%, p = .020) but not with lithium treatment (60.0%, p = .165). The median time to onset of subsyndromal symptoms for lamotrigine (N = 223), lithium (N = 164), and placebo (N = 188) was 15, 15, and 9 days, respectively. Compared with placebo, both lamotrigine and lithium significantly delayed the time from randomization to onset of subsyndromal symptoms (p = .046, lamotrigine vs. placebo; p = .033, lithium vs. placebo; p = .763, lamotrigine vs. lithium) and the time from onset of subsyndromal symptoms to subsequent mood episode (p = .037, lamotrigine vs. placebo; p = .023, lithium vs. placebo; p = .845, lamotrigine vs. lithium). Agreement between the polarities of the first-observed subsyndromal symptom and subsequent intervention for mood episode was statistically significant (p < .001).Subsyndromal symptoms are common during maintenance treatment and appear to be associated with relapse into an episode of the same polarity. Both lithium and lamotrigine delayed the onset of subsyndromal symptoms and the time from onset of subsyndromal symptoms to subsequent relapse. Further study to assess whether treatment intervention can minimize subsyndromal symptoms or prevent relapse is encouraged.

Abstract

Studies of patients with unipolar depression have demonstrated a relationship between subthreshold depressive symptoms and impairment in role functioning. Research examining this relationship in persons with bipolar disorder is rare. This study sought to evaluate the association between subsyndromal depressive symptoms and role functioning in subjects with bipolar disorder.759 adult outpatients with a DSM-IV diagnosis of bipolar disorder were entered into this study at 7 different sites in the Stanley Foundation Bipolar Network (SFBN) beginning in March 1996 and ending in November 2002 and were followed longitudinally for assessment of their course of illness. Subsyndromal depression was operationalized using cutoff scores on the Inventory for Depressive Symptomatology-Clinician Rated (IDS-C), and patients were divided into 3 groups: not depressed (IDS-C score < 13), subsyndromally depressed (IDS-C score 13 to 27), and syndromally depressed (IDS-C score >or= 28). Groups were compared using a series of chi(2) analyses on degree of role function impairment across 4 role domains (work, home duties, family life, and friendships) from the Life Functioning Questionnaire. Logistic regression was used to estimate the probability of any impairment in life functioning based on severity of depressive symptoms.Subsyndromally depressed patients were significantly more likely than those not depressed to report impairment in their work and home functioning roles, as well as impairment in relations with family and friends (p < .001). Across all domains of role function, the proportion of patients impaired in the subsyndromally depressed group was more similar to the syndromally depressed group than to the not depressed group.These findings clearly demonstrate the public health significance of subsyndromal depression in the bipolar population. The most appropriate interventions for subsyndromal depressive symptoms in patients with bipolar disorder remain to be determined.

Abstract

Several lines of evidence suggest that omega-3 fatty acids may be important in the pathophysiology, treatment or prevention of bipolar disorder (BD). Electronic and manual searches were conducted in order to review the literature relevant to the etiology and treatment of BDs with omega-3 fatty acids. We also present data from a randomized, double-blind, placebo-controlled pilot study conducted at three sites (N = 10) comparing an omega-3 fatty acid (docosahexaenoic acid, DHA) versus placebo, added to psychosocial treatment for women with BD who chose to discontinue standard pharmacologic treatment while attempting to conceive. While some epidemiologic and preclinical data support the role of omega-3 fatty acids in BD, clinical trials to date have yielded conflicting results. In our pilot study of 10 Caucasian women taking DHA while attempting to conceive (BP1 = 9, BPII = 1), age 27-42 years, DHA was well tolerated and suggests that a larger study would be feasible. The elucidation of the potential role of omega-3 fatty acids as a treatment for BD requires further study. The current data are not sufficient to support a recommendation of monotherapy treatment as a substitute for standard pharmacologic treatments. However, judicious monotherapy in selected clinical situations, or adjunctive use, may be warranted pending further data from adequately powered controlled clinical trials. Our pilot trial of DHA in women who plan to stop conventional psychotropics in order to conceive suggests that such trials are feasible.

Abstract

This article describes the implementation and utilization of the patient and family education program (PFEP) component of the Texas Medication Algorithm Project (TMAP). The extent of participation, types of psychoeducation received, and predictors of receiving at least a minimum level of education are presented.TMAP included medication guidelines, a dedicated clinical coordinator, standardized assessments of symptoms and side effects, uniform documentation, and a PFEP. The PFEP includes phased, multimodal, disorder-specific educational materials for patients and families. Participants were adult outpatients of 1 of 7 community mental health centers in Texas that were implementing the TMAP disease management package. Patients had DSM-IV clinical diagnoses of major depressive disorder, with or without psychotic features; bipolar I disorder or schizoaffective disorder, bipolar type; or schizophrenia or schizoaffective disorder. Assessments were administered by independent research coordinators. Study data were collected between March 1998 and March 2000, and patients participated for at least 1 year.Of the 487 participants, nearly all (95.1%) had at least 1 educational encounter, but only 53.6% of participants met criteria for "minimum exposure" to individual education interventions. Furthermore, only 31.0% participated in group education, and 42.5% had a family member involved in at least 1 encounter. Participants with schizophrenia were less involved in the PFEP across multiple indicators of utilization. Diagnosis, intensity of symptoms, age, and receipt of public assistance were related to the likelihood of exposure to minimum levels of individual education.Despite adequate resources and infrastructure to provide PFEP, utilization was less than anticipated. Although implementation guidelines were uniform across diagnoses, participants with schizophrenia experienced less exposure to psychoeducation. Recommendations for improving program implementation and modification of materials are discussed.

Abstract

Few studies have examined the relative risks of switching into hypomania or mania associated with second-generation antidepressant drugs in bipolar depression.To examine the relative acute effects of bupropion, sertraline and venlafaxine as adjuncts to mood stabilisers.In a 10-week trial, participants receiving out-patient treatment for bipolar disorder (stratified for rapid cycling) were randomly treated with a flexible dose of one of the antidepressants, or their respective matching placebos, as adjuncts to mood stabilisers.A total of 174 adults with bipolar disorder I, II or not otherwise specified, currently in the depressed phase, were included. All three antidepressants were associated with a similar range of acute response (49-53%) and remission (34-41%). There was a significantly increased risk of switches into hypomania or mania in participants treated with venlafaxine compared with bupropion or sertraline.More caution appears indicated in the use of venlafaxine rather than bupropion or sertraline in the adjunctive treatment of bipolar depression, especially if there is a prior history of rapid cycling.

Abstract

To assess the efficacy of lamotrigine or lithium in preventing mood recurrence (i.e., a new mood episode) in bipolar disorder.Data from bipolar I patients with relapses (i.e., mood episodes having the same polarity as the index episode within 90 or 180 days of randomization) were excluded from post hoc efficacy analyses of two 18-month, placebo-controlled maintenance trials of lamotrigine and lithium.Both lamotrigine and lithium were more effective than placebo in delaying the time to intervention for any mood episode (depression, mania, hypomania, or mixed) when relapses that occurred in the first 90 days were excluded from the analyses (p = .002, lamotrigine vs. placebo; p = .010, lithium vs. placebo). Results were similar when patients with mood episodes within 180 days of randomization were excluded.Both lamotrigine and lithium maintenance therapy protected against mood episode recurrence in bipolar I disorder.

Abstract

Preliminary evidence suggests that valproate is associated with isolated features of polycystic ovarian syndrome (PCOS), while contradictory data support an association between epilepsy and PCOS. The development of PCOS features after initiation of valproate was therefore examined in women with bipolar disorder using a standardized definition of PCOS.Three hundred women 18 to 45 years old with bipolar disorder were evaluated for PCOS at 16 Systematic Treatment Enhancement for Bipolar Disorder sites. A comparison was made between the incidence of hyperandrogenism (hirsutism, acne, male-pattern alopecia, elevated androgens) with oligoamenorrhea that developed while taking valproate versus other anticonvulsants (lamotrigine, topiramate, gabapentin, carbamazepine, oxcarbazepine) and lithium. Medication and menstrual cycle histories were obtained, and hyperandrogenism was assessed.Among 230 women who could be evaluated, oligoamenorrhea with hyperandrogenism developed in 9 (10.5%) of 86 women on valproate and in 2 (1.4%) of 144 women on a nonvalproate anticonvulsant or lithium (relative risk 7.5, 95% confidence interval [CI] 1.7-34.1, p = .002). Oligoamenorrhea always began within 12 months of valproate use.Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism. Monitoring for reproductive-endocrine abnormalities is important when starting and using valproate in reproductive-aged women. Prospective studies are needed to elucidate risk factors for development of PCOS on valproate.

Abstract

Disease management systems that incorporate medication algorithms have been proposed as cost-effective means to offer optimal treatment for patients with severe and chronic mental illnesses. The Texas Medication Algorithm Project was designed to compare health care costs and clinical outcomes between patients who received algorithm-guided medication management or usual care in 19 public mental health clinics.This longitudinal cohort study for patients with major depression (N=350), bipolar disorder (N=267), and schizophrenia (N=309) applied a multi-part declining-effects cost model. Outcomes were assessed by the Inventory of Depressive Symptomatology and the Brief Psychiatric Rating Scale.Compared with patients in usual care, patients in algorithm-based care incurred higher medication costs and had more frequent physician visits, although these differences often became smaller with time. For major depression, algorithm-based care achieved better outcomes sustainable with time but at higher agency and non-agency costs (mixed cost-effective). For bipolar disorder, patients in algorithm-based management achieved better outcomes at lower agency costs (cost-effective). For schizophrenia, patients in algorithm-based care achieved better outcomes that diminished with time, with no detectable difference in health care costs (cost-effective).Cost outcomes of algorithm-based care and usual care varied by disorder and over time. For bipolar disorder and schizophrenia, algorithm-based care improved outcomes without higher costs for health care services. For major depression, substantively better and sustained outcomes were obtained but at greater costs.

Abstract

The authors compared the switch rate into hypomania/mania in depressed patients treated with second-generation antidepressants who had either bipolar I or bipolar II disorder.In a 10-week trial, 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, two with bipolar disorder not otherwise specified) were treated with one of three antidepressants as an adjunct to mood stabilizers. The patients' switch rates were assessed. Switch was defined as a Young Mania Rating Scale (YMRS) score >13 or a Clinical Global Impression (CGI) mania score > or =3 (mildly ill).Depressed subjects with bipolar II disorder had a significantly lower acute switch rate into hypomania/mania when either YMRS or CGI criteria were used to define switch.These data suggest that depressed patients with bipolar II disorder are less vulnerable than those with bipolar I disorder to switch into hypomania/mania when treated with an antidepressant adjunctive to a mood stabilizer.

Abstract

The authors examined the comparative risks of switches in mood polarity into hypomania or mania during acute and continuation trials of adjunctive antidepressant treatment of bipolar depression.One hundred fifty-nine patients with bipolar I disorder or bipolar II disorder participated in a total of 228 acute (10-week) randomized trials of bupropion, sertraline, or venlafaxine as an adjunct to a mood stabilizer. Patients in 87 of these trials entered continuation treatment for up to 1 year. Antidepressant response and the occurrence of subthreshold brief hypomania (emergence of brief hypomania [at least 1 but <7 days] or recurrent brief hypomania) and threshold switches (emergence of full-duration hypomania [> or =7 days] or mania) were blindly assessed by using clinician-rated daily reports of mood-associated dysfunction on the National Institute of Mental Health Life Chart Method.Threshold switches into full-duration hypomania and mania occurred in 11.4% and 7.9%, respectively, of the acute treatment trials and in 21.8% and 14.9%, respectively, of the continuation trials. The rate of threshold switches was higher in the 169 trials in patients with bipolar I disorder (30.8%) than the 59 trials in patients with bipolar II disorder (18.6%). The ratio of threshold switches to subthreshold brief hypomanias was higher in both the acute (ratio=3.60) and continuation trials (ratio=3.75) of venlafaxine than in the acute and continuation trials of bupropion (ratios=0.85 and 1.17, respectively) and sertraline (ratios=1.67 and 1.66, respectively). In only 37 (16.2%) of the original 228 acute antidepressant trials, or in only 23.3% of the patients, was there a sustained antidepressant response in the continuation phase in the absence of a threshold switch.Adjunctive treatment with antidepressants in bipolar depression was associated with substantial risks of threshold switches to full-duration hypomania or mania in both acute and long-term continuation treatment. Of the three antidepressants included in the study, venlafaxine was associated with the highest relative risk of such switching and bupropion with the lowest risk.

Abstract

Despite increasing adoption of clinical practice guidelines in psychiatry, there is little measurement of provider implementation of these recommendations, and the resulting impact on clinical outcomes. The current study describes one effort to measure these relationships in a cohort of public sector out-patients with bipolar disorder.Participants were enrolled in the algorithm intervention of the Texas Medication Algorithm Project (TMAP). Study methods and the adherence scoring algorithm have been described elsewhere. The current paper addresses the relationships between patient characteristics, provider experience with the algorithm, provider adherence, and clinical outcomes. Measurement of provider adherence includes evaluation of visit frequency, medication choice and dosing, and response to patient symptoms. An exploratory composite 'adherence by visit' score was developed for these analyses.A total of 1948 visits from 141 subjects were evaluated, and utilized a two-stage declining effects model. Providers with more experience using the algorithm tended to adhere less to treatment recommendations. Few patient factors significantly impacted provider adherence. Increased adherence to algorithm recommendations was associated with larger decreases in overall psychiatric symptoms and depressive symptoms over time, but did not impact either immediate or long-term reductions in manic symptoms.Greater provider adherence to treatment guideline recommendations was associated with greater reductions in depressive symptoms and overall psychiatric symptoms over time. Additional research is needed to refine measurement and to further clarify these relationships.

Abstract

Rapid cycling in bipolar disorder has been associated with greater morbidity. We examine whether rapid cycling affects treatment response to olanzapine or divalproex in acute mania.A post hoc analysis of a 47-week, randomized, double-blind study compared olanzapine (5-20 mg/day) to divalproex sodium (500-2500 mg/day) for bipolar manic or mixed episodes (N=251). Young Mania Rating Scale (YMRS) scores > or = 20 were required for inclusion. Patients were classified at study entry as "rapid cyclers" if they experienced > or = 4 episodes within the last year. A repeated measures analysis of variance was used to analyze YMRS change from baseline.A significant three-way interaction (cycling frequency by medication by visit) was found when modeling change in YMRS total scores. For patients with bipolar I disorder identified as rapid cyclers, mania improvement across the trial did not differ significantly between treatment groups (p=0.181). Among non-rapid cyclers, olanzapine-treated patients had significantly greater YMRS improvement than divalproex-treated patients across the trial (p<0.001) and at most time points. Among olanzapine-treated patients, non-rapid cyclers experienced numerically greater YMRS improvement than rapid cyclers throughout the trial; statistically significant differences occurred at weeks 11, 15 and 39. In contrast, among divalproex-treated patients, YMRS scores were significantly better in rapid cyclers than non-rapid cyclers during the first two study weeks but were comparable thereafter. A similar pattern was seen in Clinical Global Impressions-Mania Severity scores. Hamilton Depression scores in rapid versus non-rapid cycling patients differed at some time points but not over the entire trial and differences by cycling status were not treatment-specific.Apart from the post hoc nature of the analyses, there were high dropout rates in both groups, and cycle frequency was not taken into account.Rapid cycling patients did less well over long-term treatment than non-rapid cycling patients. Among rapid cycling patients, olanzapine and divalproex appear similarly effective against manic symptoms; however, among non-rapid cycling patients, olanzapine-treated patients experienced superior mania improvement. Olanzapine-treated, non-rapid cyclers experienced greater mania improvement than rapid cyclers. The converse was true of divalproex-treated patients early in treatment.

Abstract

The staff of the American Psychiatric Association (APA), the American Psychiatric Institute for Research and Education (APIRE), and a national panel of experts in bipolar disorder and practice guideline development have collaborated to generate a set of quality of care indicators for the pharmacologic and psychosocial treatment of bipolar disorder. The indicators were derived from APA's evidence-based Practice Guideline for the Treatment of Patients with Bipolar Disorder, 2002 (1) and the Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder, 2000 (2) These quality indicators can be used for quality monitoring, benchmarking, and quality improvement efforts across health plans, systems of care, and health care providers to improve quality and outcomes of care for patients with bipolar disorder.

Abstract

The prevalence of depressive symptoms co-occurring with hypomanic symptoms has not been quantified. Whether there is a greater likelihood for women to experience mixed symptoms has not been resolved.To determine whether mixed hypomania is observed more frequently than euphoric hypomania and whether a sex effect exists in patients with bipolar disorder.Academic research settings in the United States (4 sites) and Europe (3 sites).Subjects were enrolled in a naturalistic prospective study after providing written informed consent.Mixed hypomania was defined at a given visit as a Young Mania Rating Scale score of 12 or higher and an Inventory of Depressive Symptomatology-Clinician-Rated Version score of 15 or higher. Given partial overlap of items from these scales, exploratory analyses were completed assessing instrument overlap affecting the findings.In 908 patients, 14 328 visits over 7 years were evaluated. Patients with bipolar I disorder were significantly more likely to experience hypomania than those with bipolar II disorder. Of all 1044 visits by patients with hypomanic symptoms, 57% met criteria for mixed hypomania. The likelihood of depression was significantly greater for women during hypomania (P

Abstract

To detect risk factors for rapid cycling in bipolar disorder, the authors compared characteristics of rapid-cycling and non-rapid-cycling patients both from a categorical and a dimensional perspective.Outpatients with bipolar I disorder (N=419), bipolar II disorder (N=104), and bipolar disorder not otherwise specified (N=16) were prospectively evaluated with daily mood ratings for 1 year. Subjects were classified as having rapid cycling (defined by the DSM-IV criterion of four or more manic or depressive episodes within 1 year) or not having rapid cycling, and the two groups' demographic and retrospective and prospective illness characteristics were compared. Associated factors were also evaluated in relationship to episode frequency.Patients with rapid cycling (N=206; 38.2%) significantly differed from those without rapid cycling (N=333) with respect to the following independent variables: history of childhood physical and/or sexual abuse, bipolar I disorder subtype, number of lifetime manic or depressive episodes, history of rapid cycling, and history of drug abuse. The prevalence of these characteristics increased progressively with episode frequency. The proportion of women was greater than the proportion of men only among patients with eight or more episodes per year. The average time spent manic/hypomanic increased as a function of episode frequency, but the average time spent depressed was comparable in patients with one episode and in those with more than one episode. Brief episodes were as frequent as full-duration DSM-IV-defined episodes.A number of heterogeneous risk factors were progressively associated with increasing episode frequency. Depression predominated in all bipolar disorder patients, but patients with rapid cycling were more likely to be characterized by manic features. The findings overall suggest that rapid cycling is a dimensional course specifier arbitrarily defined on a continuum of episode frequency.

Abstract

A panel consisting of academic psychiatrists and pharmacist administrators of the Texas Department of State Health Services (formerly Texas Department of Mental Health and Mental Retardation), community mental health physicians, advocates, and consumers met in May 2004 to review new evidence in the pharmacologic treatment of bipolar I disorder (BDI). The goal of the consensus conference was to update and revise the current treatment algorithm for BDI as part of the Texas Implementation of Medication Algorithms, a statewide quality assurance program for the treatment of major psychiatric illness. The guidelines for evaluating possible medications, the criteria for selection and ranking, and the updated algorithms are described.Principles from previous consensus conferences were reviewed and amended. Medication algorithms for the acute treatment of hypomanic/manic or mixed and depressive episodes in BDI were developed after examining recent efficacy and safety and tolerability data. Recommendations for maintenance treatments were developed.The panel updated the 2 primary algorithms (hypomanic/manic/mixed and depressive) based on clinical evidence for efficacy, tolerability, and safety developed since 2000. Expert consensus was utilized where clinical evidence was limited. Prevention of new episodes or prophylaxis treatment recommendations were developed based on recent data from longer-term trials. Maintenance recommendations are provided as levels versus a specified staged algorithm, as for acute treatment, due to the relatively limited database to inform treatment.These algorithms for the treatment of BDI represent the recommendations based on the most recent evidence available. These recommendations are meant to provide a framework for clinical decision making, not to replace clinical judgment. As with any algorithm, treatment practices will evolve beyond the recommendations of this consensus conference as new evidence and additional medications become available.

Abstract

Our goal was to suggest a factor structure for the Brief Psychiatric Rating Scale Expanded Version (BPRS-E) based upon a large and diverse sample and to determine which of the new items improved the factors derived from the 18-item version of the scale that have been used in clinical research for decades. We investigated the consistency of our proposed model over time and across demographic groups. As part of the Texas Medication Algorithm Project, the BPRS-E was administered to a total of 1440 psychiatric outpatients in three different diagnostic groups on multiple occasions. The sample was randomly split so that exploratory factor analysis could be done with the first half, and the model could be confirmed on the second half. A four-factor structure including factors assessing depression/anxiety, psychosis, negative symptoms, and activation was found. For each factor, we specify items in the expanded version that added to the breadth of the commonly used clinical factors while improving or maintaining goodness of fit and reliability. The final model proposed was consistent over time and across diagnosis, phase of illness, age, gender, ethnicity, and level of education. The BPRS-E has a stable four-factor structure, making it useful as a clinical outcome measure.

Abstract

This study examined the reproductive function and prevalence of polycystic ovary syndrome (PCOS) in women with bipolar disorder taking antimanic medications.Women aged 18-45 treated for bipolar disorder and not taking steroid contraceptives were recruited to complete questionnaires about their menstrual cycle and to provide blood samples for measurement of a range of reproductive endocrine and metabolic hormone levels. Eighty women participated in completing the questionnaires and 72 of them provided blood samples.Fifty-two of the 80 women (65%) reported current menstrual abnormalities, 40 of which (50%) reported one or more menstrual abnormalities that preceded the diagnosis of bipolar disorder. Fifteen women (38%) reported developing menstrual abnormalities since treatment for bipolar disorder, 14 of which developed abnormalities since treatment with valproate (p = 0.04). Of the 15 patients reporting menstrual abnormalities since starting medication, 12 (80%) reported changes in menstrual flow (heavy or prolonged bleeding) and five (33%) reported changes in cycle frequency. No significant differences were observed between women receiving or not receiving valproate in mean levels of free or total serum testosterone levels. This was true for the total sample and for the sub-group without preexisting menstrual problems. However, within the valproate group, duration of use was significantly correlated with free testosterone levels (r = 0.33, p = 0.02). Three of the 50 women (6%) taking VPA, and 0% of the 22 taking other antimanic medications, met criteria for PCOS (p = 0.20). Other reproductive and metabolic values outside the normal range across treatment groups included elevated 17 alpha-OH progesterone levels, luteinizing hormone: follicle-stimulating hormone ratios, homeostatic model assessment (HOMA) values, and low estrogen and dehydroepiandrosterone sulfate (DHEAS) levels. Preexisting menstrual abnormalities predicted higher levels of 17 alpha-OH progesterone, free testosterone, and estrone as well as development of new menstrual abnormalities. Body mass index (BMI) was significantly positively correlated with free testosterone levels and insulin resistance (HOMA) across all subjects, regardless of medication used.Rates of menstrual disturbances are high in women with bipolar disorder and, in many cases, precede the diagnosis and treatment for the disorder. Treatment with valproate additionally contributes significantly to the development of menstrual abnormalities and an increase in testosterone levels over time. A number of bipolar women, regardless of type of medication treatment received, have reproductive and metabolic hormonal abnormalities, yet the etiology of such abnormalities requires further study. Women with preexisting menstrual abnormalities may represent a group at risk for development of reproductive dysfunction while being treated for bipolar disorder.

Abstract

The response of 62 outpatients with DSM-IV bipolar disorders to open-label adjunctive zonisamide was evaluated in a prospective 8-week acute trial, followed by a 48-week continuation trial, conducted from June 2001 through May 2002.During the acute trial, response to zonisamide was assessed weekly for the first 4 weeks and every 2 weeks for the second 4 weeks with the Clinical Global Impressions scale modified for bipolar illness (CGI-BP), the Young Mania Rating Scale (YMRS), and the Inventory for Depressive Symptomatology (IDS). During the continuation trial, patients were assessed with these scales every 4 weeks. Patients' weights and side effects were also evaluated. Outcome measures were analyzed with repeated-measures analyses of variance.Patients with manic symptoms at study entry (N = 34) displayed significant reductions in CGI-BP-Mania Severity and YMRS scores in the acute and continuation (N = 19) trials (p values < .0001 and < .001, respectively). Patients with depressive symptoms at study entry (N = 22) showed significant decreases in CGI-BP-Depression Severity and IDS scores in the acute trial (p values < .001 and < .05, respectively), but only 9 patients entered the continuation trial. Among these 9 patients, maintenance of anti-depressant response was mostly maintained. Initially euthymic patients (N = 6) showed no change in any rating scale scores acutely, but 2 of 4 patients who entered the continuation trial developed depressive symptoms. The 62 patients as a group showed significant weight loss in both trials (p values < .001). However, 20 patients (32%) discontinued zonisamide for worsening mood symptoms.Adjunctive zonisamide was associated with beneficial effects on mood and body weight in some patients with bipolar disorders, but was also associated with a high discontinuation rate due to worsening mood symptoms. Double-blind, placebo-controlled studies are necessary to determine zonisamide's thymoleptic properties, if any, in bipolar disorders.

Abstract

The purpose of this study was to assess the evidence base for the efficacy of light therapy in treating mood disorders.The authors systematically searched PubMed (January 1975 to July 2003) to identify randomized, controlled trials of light therapy for mood disorders that fulfilled predefined criteria. These articles were abstracted, and data were synthesized by disease and intervention category.Only 13% of the studies met the inclusion criteria. Meta-analyses revealed that a significant reduction in depression symptom severity was associated with bright light treatment (eight studies, having an effect size of 0.84 and 95% confidence interval [CI] of 0.60 to 1.08) and dawn simulation in seasonal affective disorder (five studies; effect size=0.73, 95% CI=0.37 to 1.08) and with bright light treatment in nonseasonal depression (three studies; effect size=0.53, 95% CI=0.18 to 0.89). Bright light as an adjunct to antidepressant pharmacotherapy for nonseasonal depression was not effective (five studies; effect size=-0.01, 95% CI=-0.36 to 0.34).Many reports of the efficacy of light therapy are not based on rigorous study designs. This analysis of randomized, controlled trials suggests that bright light treatment and dawn simulation for seasonal affective disorder and bright light for nonseasonal depression are efficacious, with effect sizes equivalent to those in most antidepressant pharmacotherapy trials. Adopting standard approaches to light therapy's specific issues (e.g., defining parameters of active versus placebo conditions) and incorporating rigorous designs (e.g., adequate group sizes, randomized assignment) are necessary to evaluate light therapy for mood disorders.

Abstract

Levetiracetam is a recently approved, well-tolerated anticonvulsant with a unique mechanism of action yielding efficacy in treatment-refractory seizure disorders and positive effects in an animal model of mania. Given the effectiveness of a range of other anticonvulsants in bipolar disorder, we sought to evaluate levetiracetam in patients with treatment-resistant illness.Thirty-four patients received 500 to 1000 mg of levetiracetam titrated to a target dose of 2000 mg/day (maximum dose = 3000 mg/day) as open, adjunctive treatment for clinically significant symptoms of depression (N = 13), mania (N = 7), or cycling (N = 14) despite ongoing treatment with mood stabilizers. Inventory for Depressive Symptomatology-Clinician version (IDS-C), Young Mania Rating Scale (YMRS), and Clinical Global Impressions scale for use in Bipolar Illness ratings were completed at each visit for 8 weeks, and partial responders were offered continuation treatment. Data were collected from July 2001 to December 2002.Five of 16 (31%; 13 depressed, 3 cycling) patients with initial depressive symptoms met the criterion for remission (IDS-C score of < or = 13) at last observation. All of these patients were less severely ill at baseline, whereas none of those more severely depressed at baseline responded. The majority of the 16 patients (7 manic, 9 cycling) with manic symptoms at baseline showed improvement in the YMRS in the first 2 weeks. While 7 of the 16 (44%) patients met the criterion for manic response and remission at last observation, 4 showed intervening periods of moderate to marked exacerbation. Levetiracetam was weight neutral.Other pilot trials should explore possible areas of psychotropic action of levetiracetam prior to the conduct of more controlled clinical trials.

Abstract

Open, uncontrolled studies suggest clozapine can have mood-stabilizing effects in treatment-resistant bipolar disorder. Unfortunately, the side effect profile limits clozapine's use at high doses. We report a series of nine bipolar I disorder patients who improved on relatively low doses of clozapine add-on therapy (250 mg or lower). Retrospectively abstracted clinical data identified nine patients with bipolar I disorder, as defined by DSMIV criteria, treated with low-dose clozapine at inpatient and outpatient settings. Monthly symptom evaluations were collected prospectively using standard assessments. Symptoms of mania and mood lability improved in all patients. Three patients demonstrated striking mood stabilization and returned to previous levels of functioning; five patients evidenced moderate improvement in mood stabilization and functioning; and one patient showed a minimal response. Overall, clozapine did not have a significant antidepressant effect. The mean clozapine dose at the end of the study was 156.3 +/- 77.6 mg/day, and duration of treatment was 12 months. Residual side effects were mild. The symptomatic improvement in these prospectively evaluated patients is consistent with our clinical impression in the majority of patients with bipolar disorder taking clozapine.

Abstract

Bipolar depression has started to receive more attention in clinical trials only relatively recently, despite the fact that patients spend more time in the depressed phase than in the manic phase of bipolar disorder. The diagnosis and management of bipolar depression are challenging, and many patients are undiagnosed or misdiagnosed due to symptom similarities with unipolar depression or other illnesses and/or comorbidities. Untreated or inappropriately treated bipolar depression adds to the burden of illness and is associated with a greater risk of suicide. Treatment options include lithium, lamotrigine, atypical antipsychotics, and traditional antidepressants, such as the selective serotonin reuptake inhibitors. However, traditional antidepressants are recommended with caution due to their potential risk of switching patients into mania. Some atypical antipsychotics have shown efficacy in bipolar depression, although longer-term studies are warranted. The choice of treatment for different subgroups of patients with bipolar depression, including those with comorbid anxiety, may vary and also needs further study. Other important issues that require further investigation include the recognition of the core features of bipolar depression and the threshold symptoms for treatment, as well as the optimal treatment choices for monotherapy or combination therapy, and acute versus long-term management of bipolar depression.

Abstract

"Conventional" antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), bupropion, or serotonin-norepinephrine reuptake inhibitors, are not recommended as monotherapy for bipolar depression. Although they are likely to provide effective symptom relief in combination with mood stabilizers, the risk of precipitating a switch to mania often complicates their use even as combination therapy. Recently, 2 psychotropic medications approved for treating acute mania, olanzapine and quetiapine, have also been shown to possess antidepressant activity without destabilizing mood and, as such, are potential mood stabilizers. This article aims to review the mechanism of action of conventional antidepressants and newer agents that are effective in the treatment of bipolar depression. A number of mechanisms have been postulated to play a role in the effective treatment of bipolar depression, including targets as diverse as serotonin (5-HT), norepinephrine, dopamine, gamma-aminobutyric acid (GABA), glutamate, and various second messenger signaling pathways. A review of the data reveals an important point of commonality among the antidepressant treatments, olanzapine, and quetiapine. Antidepressant treatments, such as norepinephrine reuptake inhibitors, SSRIs, and electroconvulsive therapy, induce a reduction of 5-HT(2A) receptors. Both olanzapine and quetiapine not only are antagonists at this receptor but also induce downregulation of 5-HT(2A) receptors. It is possible that the antidepressant efficacy of these agents is mediated by this receptor, while the additional benefit of olanzapine and quetiapine over unimodal antidepressant treatments, in terms of stabilizing mood, may be provided by their concomitant dopamine D(2) antagonism. Further studies should be conducted to examine these hypotheses.

Abstract

Sleep disturbances are strongly associated with mood disorders, although the majority of data have been obtained in patients with major depressive disorder. Studies reporting results in bipolar disorder are few, and results have not been consistent. Clozapine is a prototype of atypical antipsychotics, which is effective in improving symptoms of manic episodes in patients with bipolar disorder, or schizoaffective disorder, bipolar type and has been shown to influence sleep in other psychiatric disorders. The present study evaluated the sleep effects of clozapine in bipolar and schizoaffective disorders.Participants were 11 women and 4 men (range:28-53 years of age, mean 40.9+/-8.6 years), all with a history of mania by DSM-IV criteria for either bipolar I disorder or schizoaffective disorder, bipolar type. They participated in a sleep study at baseline and again after 6 months initiation of clozapine add-on therapy.Sleep latency was longer on clozapine and the number of awakenings were increased, whereas time in bed (TIB) and total sleep period (TSP) were increased (range: F=6.2-17.9; df=l,12; p<0.05). Although none of the individual sleep stage showed significant treatment changes, both Stage 2 and slow-wave sleep were increased and Stage 2 decreased on clozapine. Subjective sleep measures improved on clozapine with a small but significant improvement in how rested patients felt upon awakening (t=-2.1; df=26; p<0.05).Clozapine prolonged sleep latency, improved restedness, and increased total sleep time. Although lack of a control group limits interpretation of these results, they are in general agreement with studies in other psychiatric populations, and support the view that clozapine is primarily a NREM sleep enhancer. The improvement in restedness may be of positive clinical consequence.

Abstract

Acute manic episodes in bipolar disorder require rapid and effective relief. Pharmacotherapy has traditionally involved mood stabilizers such as lithium or divalproex. Evidence for the efficacy of atypical antipsychotics to treat bipolar mania, either as monotherapy or in combination with traditional mood-stabilizing agents, has increased in recent years. Since the combination of an atypical agent and a traditional mood stabilizer is generally well tolerated, it represents a first-line approach for the treatment of severe and treatment-resistant mania. Atypical antipsychotics have a superior neurological tolerability profile compared with typical antipsychotics and are preferentially recommended in most treatment guidelines. The atypical agents, olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole, have demonstrated efficacy in bipolar mania in large randomized, controlled studies, and offer efficacy across a broader range of symptoms than typical antipsychotics, and may even have mood-stabilizing properties traditionally associated with lithium and divalproex. Olanzapine, risperidone and quetiapine have been shown to be effective for manic episodes both as monotherapy and in combination with other agents such as lithium and divalproex. Although the tolerability profiles of atypicals as a class are superior to those of conventional antipsychotics, there are differences among the atypical agents in their propensity to cause certain adverse events such as extrapyramidal symptoms (EPS) and weight gain, particularly in the long-term. The ultimate choice of the atypical agent will depend on the patient's individual needs, but atypical antipsychotics are clinically effective options for achieving mood stabilization in the treatment of acute bipolar mania.

Abstract

Residual depression and medication-induced sedation remain significant problems for many patients with bipolar disorder (BD). Some evidence indicates that bipolar depression may be more responsive to dopaminergic agents, suggesting that adjunctive stimulant medication may be an effective treatment for bipolar depression as well as for medication-induced sedation. However, there are few data regarding the use of these medications in BD, likely due in part to concerns regarding potential stimulant-induced switching and stimulant abuse.In order to evaluate the effectiveness and safety of psychostimulants in BD, we retrospectively reviewed the cases of eight consecutive individuals from our clinic (five with bipolar I and three with bipolar II) who received adjunctive stimulants (either methylphenidate or amphetamine) within the last 2 years. Primary target symptoms of stimulant therapy included residual depression and medication-induced sedation. The degree of clinical change in target symptoms was estimated, and the Clinical Global Impression-BP Version scale (CGI-BP) was used to evaluate the overall severity of illness at baseline, 6 months after stimulant initiation, and at last visit.The eight patients generally showed moderate clinical improvement in their target symptoms and substantial improvement of overall bipolar illness (mean change in CGI-BP overall score 2.9). There was no evidence of stimulant-induced switching or abuse. The stimulants were well tolerated.The present case series suggests that adjunctive stimulants may be a reasonable therapeutic option for treating residual depression and medication-induced sedation in some patients. Controlled trials are needed to assess the safety and effectiveness of stimulant augmentation in BD.

Abstract

The purpose of the study was to examine potential correlates of outcome in patients treated for bipolar disorder.During a 1-year period, 258 patients with DSM-IV bipolar disorder or schizoaffective disorder were rated with the prospective NIMH-Life Chart Method, which characterizes each day in terms of the severity of manic and depressive symptoms on the basis of patients' mood-related impairment in their usual educational, social, or occupational roles. Mean ratings for the severity of mania, depression, and overall bipolar illness and the number of manic, depressive, and overall illness episodes were calculated. Potential risk factors were assessed at the start of the study, and multivariate linear regression analysis was used to determine the correlates of the six 1-year outcome measures.Three of the six outcome measures were largely independent of each other and were used in the analysis. The mean rating for severity of mania was associated with comorbid substance abuse, history of more than 10 prior manic episodes, and poor occupational functioning at study entry. The mean rating for severity of depression was associated with a history of more than 10 prior depressive episodes and poor occupational functioning at study entry. The total number of overall illness episodes was associated with a positive family history of drug abuse, a history of prior rapid cycling, and poor occupational functioning. In addition, the mean rating for severity of mania and the total number of overall illness episodes were both initially associated with a history of childhood abuse, but these relationships were lost with the addition of other illness variables to the analysis.Clinicians who treat patients with bipolar disorder should consider a family history of drug abuse, a history of childhood abuse, prior course of illness, comorbid substance abuse, and occupational functioning in determining prognosis and setting goals for further treatment.

Abstract

Rapid cycling (RC) bipolar disorder (BD) patients often do not respond fully to mood-stabilizers. Atypical antipsychotics including clozapine may be good candidates as an alternative mood-stabilizer for these patients.Twenty-eight treatment-resistant patients with either Bipolar Disorder Type I (n = 20), or Schizoaffective Disorder Bipolar Type (n = 8) received clozapine add-on therapy. Patients were followed for up to 1 year. Patients were seen monthly and assessed on a number of symptom domains.Fifteen of 28 patients met RC criteria. Differences between groups was non-significant for reported age of onset, age at study entry, past history of treatment or hospitalization, or diagnosis. However, significantly more women were RC. More than 80% of patients in either group showed at least some improvement over the 1-year study. Random regression analyses found the non-rapid cycling (NRC) group experienced significantly greater improvement than RC patients (p < 0.0001).Clozapine is more effective in NRC patients with a history of mania in comparison to patients with a recent history of RC.

Abstract

The Texas Medication Algorithm Project is an evaluation of an algorithm-based disease management program for the treatment of the self-declared persistently and seriously mentally ill in the public mental health sector.To present clinical outcomes for patients with major depressive disorder (MDD) during 12-month algorithm-guided treatment (ALGO) compared with treatment as usual (TAU).Effectiveness, intent-to-treat, prospective trial comparing patient outcomes in clinics offering ALGO with matched clinics offering TAU.Four ALGO clinics, 6 TAU clinics, and 4 clinics that offer TAU to patients with MDD but provide ALGO for schizophrenia or bipolar disorder. Patients Male and female outpatients with a clinical diagnosis of MDD (psychotic or nonpsychotic) were divided into ALGO and TAU groups. The ALGO group included patients who required an antidepressant medication change or were starting antidepressant therapy. The TAU group initially met the same criteria, but because medication changes were made less frequently in the TAU group, patients were also recruited if their Brief Psychiatric Rating Scale total score was higher than the median for that clinic's routine quarterly evaluation of each patient.Primary outcomes included (1) symptoms measured by the 30-item Inventory of Depressive Symptomatology-Clinician-Rated scale (IDS-C(30)) and (2) function measured by the Mental Health Summary score of the Medical Outcomes Study 12-item Short-Form Health Survey (SF-12) obtained every 3 months. A secondary outcome was the 30-item Inventory of Depressive Symptomatology-Self-Report scale (IDS-SR(30)).All patients improved during the study (P

Abstract

The Brief Bipolar Disorder Symptom Scale (BDSS) is a 10-item measure of symptom severity that was derived from the 24-item Brief Psychiatric Rating Scale (BPRS24). It was developed for clinical use in settings where systematic evaluation is desired within the constraints of a brief visit. The psychometric properties of the BDSS were evaluated in 409 adult outpatients recruited from 19 clinics within the public mental health system of Texas, as part of the Texas Medication Algorithm Project (TMAP). The selection process for individual items is discussed in detail, and was based on multiple analyses, including principal components analysis with varimax rotation. Selection of the final items considered the statistical strength and factor loading of items within each of those factors as well as the need for comprehensive coverage of critical symptoms of bipolar disorder. The BDSS demonstrated good psychometric properties in this preliminary investigation. It demonstrated a strong association with the BPRS24 and performed similarly to the BPRS24 in its relationship to other symptom measures. The BDSS demonstrated superior sensitivity to symptom change, and an excellent level of agreement for classification of patients as either responders or non-responders with the BPRS24.

Abstract

Evaluate the efficacy and tolerability of quetiapine (QTP) combined with lithium (Li) or divalproex (DVP) in the treatment of acute mania.Patients were randomized to 21 days of double-blind treatment with QTP plus Li/DVP, or placebo (PBO) plus Li/DVP. QTP was rapidly dosed up to a maximum of 800 mg/day; Li was dosed to 0.7-1.0 mEq/L; or DVP to 50-100 microg/mL.Fifty-six of 91 (61.5%) individuals in the QTP + Li/DVP group compared with 49 of 100 (49%) taking PBO + Li/DVP completed the study. A significantly greater mean reduction in total Young Mania Rating Scale (YMRS) score was observed at end-point in patients receiving QTP + Li/DVP compared with those in the PBO + Li/DVP group (-13.76 versus -9.93; p = 0.021). The response rate (> or =50% YMRS improvement) was significantly higher in the QTP + Li/DVP group than in PBO + Li/DVP-treated patients (54.3% versus 32.6%; p = 0.005), as was the proportion of patients achieving clinical remission (YMRS < 12) (45.7% versus 25.8%; p = 0.007). Patients receiving QTP + Li/DVP also had a significantly greater improvement in Clinical Global Impressions-Bipolar (CGI-BP) Severity of Illness scores (-1.38 versus -0.78; p = 0.001). The mean last-week dose of QTP was 584 mg/day in patients meeting response criteria. Common adverse events (at least 10% and twice the rate of Li/DVP) in the QTP + Li/DVP group included somnolence, dry mouth, asthenia, and postural hypotension.Quetiapine combined with either Li or DVP has superior efficacy compared with Li or DVP monotherapy for treating patients with bipolar mania. Combination therapy was well-tolerated and most adverse events were mild, withdrawal because of adverse events being only 5% compared with 6% on Li or DVP monotherapy.

Abstract

Quetiapine, a new atypical antipsychotic, was added to ongoing treatment of bipolar I outpatients (n=15) for symptoms of illness (mood lability, irritability, psychosis and/or difficulty sleeping). All evaluations were prospectively obtained, with the majority of patients (n=9) showing much or very much improvement on the Clinical Global Impression for Bipolar Disorder (CGI-BP). Somatic complaints were limited. Mean (SD) duration before changes in medication regimens was 134 (100) days. Studies of the use of quetiapine in maintenance treatment of bipolar disorder are warranted.

Abstract

The adoption of treatment guidelines for complex psychiatric illness is increasing. Treatment decisions in psychiatry depend on a number of variables, including severity of symptoms, past treatment history, patient preferences, medication tolerability, and clinical response. While patient outcomes may be improved by the use of treatment guidelines, there is no agreed upon standard by which to assess the degree to which clinician behavior corresponds to those recommendations. This report presents a method to assess clinician adherence to the complex multidimensional treatment guideline for bipolar disorder utilized in the Texas Medication Algorithm Project. The steps involved in the development of this system are presented, including the reliance on standardized documentation, defining core variables of interest, selecting criteria for operationalization of those variables, and computerization of the assessment of adherence. The computerized assessment represents an improvement over other assessment methods, which have relied on laborious and costly chart reviews to extract clinical information and to analyze provider behavior. However, it is limited by the specificity of decisions that guided the adherence scoring process. Preliminary findings using this system with 2035 clinical visits conducted for the bipolar disorder module of TMAP Phase 3 are presented. These data indicate that this system of guideline adherence monitoring is feasible.

Abstract

Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder. Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse, compared with lithium or valproate alone.Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium (0.6-1.2 mmol/l) or valproate (50-125 microg/ml) received lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy) or placebo (monotherapy), and were followed in a double-masked trial for 18 months.The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse (median time to relapse: combination therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic relapse (combination therapy 163 days, monotherapy 42 days; P=0.023).Patients taking olanzapine added to lithium or valproate experienced sustained symptomatic remission, but not syndromic remission, for longer than those receiving lithium or valproate monotherapy.

Abstract

Bipolar disorder affects 0.5%-1.5% of individuals in the United States. The typical age at onset is late adolescence or early adulthood, placing women at risk for episodes throughout their reproductive years. General guidelines for the treatment of bipolar disorder are available from the American Psychiatric Association, but additional issues arise when these guidelines are applied in the treatment of peripartum women. The authors summarize knowledge regarding the management of bipolar disorder during pregnancy and the postpartum period, with a focus on managing mania, hypomania, and the psychotic components of the illness.An expert panel reviewed articles that address the management of bipolar disorder and the consequences of the use of mood stabilizers during pregnancy, and a consensus document was generated.The treatment of bipolar disorder in pregnant women involves significant challenges. Some mood stabilizers, e.g., sodium valproate and carbamazepine, are human teratogens. On the other hand, the teratogenicity associated with lithium may have been overestimated in the past.Since treatment can be managed most effectively if pregnancy is planned, clinicians should discuss the issue of pregnancy and its management with every bipolar disorder patient who has childbearing potential, regardless of future reproductive plans. Additional research should address the risks of disturbed sleep to pregnant and postpartum women with bipolar disorder, as well as structural and behavioral consequences to offspring when mood stabilizers are used during pregnancy. Longitudinal and cohort studies can promote these efforts. Given the rate of bipolar disorder in the general population, research efforts will need to be broad based and include multiple collaborating centers.

Abstract

Lamotrigine has demonstrated efficacy for the acute treatment of depression in bipolar I patients in a placebo-controlled, monotherapy study. We describe the results of a 52-week, open-label continuation of that trial.Patients meeting DSM-IV criteria for bipolar I disorder with a current major depressive episode who completed a 7-week, double-blind study of bipolar depression were offered 1 year of open-label lamotrigine therapy (flexible doses of 100-500 mg/day) in a continuation study. To maintain the acute study blind, the first 3 weeks of the continuation study remained blinded while patients previously randomly assigned to placebo were titrated to a lamotrigine dose of 50 mg/day. Patients who had been randomly assigned to lamotrigine continued at their fixed doses. Beginning at week 4, all patients received open-label lamotrigine for up to 49 additional weeks. Concomitant psychotropic medications were permitted during the open-label phase. Effectiveness (Montgomery-Asberg Depression Rating Scale [MADRS], Clinical Global Impressions-Improvement scale) and safety assessments were administered at weeks 4, 12, 24, 36, and 52. The study was conducted from June 1996 to December 1998.Of 135 patients completing the acute study, 124 (92%) entered the continuation study: 77 had received lamotrigine and 47 had received placebo in the acute study. The mean duration of lamotrigine exposure was 10.4 months, with a mean modal dose of 187 mg/day. Sixty-nine patients (56%) completed 1 year of treatment. Significant and sustained improvement from baseline was seen in mean observed MADRS scores (p

Abstract

The present study provides additional data on the psychometric properties of the 30-item Inventory of Depressive Symptomatology (IDS) and of the recently developed Quick Inventory of Depressive Symptomatology (QIDS), a brief 16-item symptom severity rating scale that was derived from the longer form. Both the IDS and QIDS are available in matched clinician-rated (IDS-C30; QIDS-C16) and self-report (IDS-SR30; QIDS-SR16) formats.The patient samples included 544 out-patients with major depressive disorder (MDD) and 402 out-patients with bipolar disorder (BD) drawn from 19 regionally and ethnicically diverse clinics as part of the Texas Medication Algorithm Project (TMAP). Psychometric analyses including sensitivity to change with treatment were conducted.Internal consistencies (Cronbach's alpha) ranged from 0.81 to 0.94 for all four scales (QIDS-C16, QIDS-SR16, IDS-C30 and IDS-SR30) in both MDD and BD patients. Sad mood, involvement, energy, concentration and self-outlook had the highest item-total correlations among patients with MDD and BD across all four scales. QIDS-SR16 and IDS-SR30 total scores were highly correlated among patients with MDD at exit (c = 0.83). QIDS-C16 and IDS-C30 total scores were also highly correlated among patients with MDD (c = 0.82) and patients with BD (c = 0.81). The IDS-SR30, IDS-C30, QIDS-SR16, and QIDS-C16 were equivalently sensitive to symptom change, indicating high concurrent validity for all four scales. High concurrent validity was also documented based on the SF-12 Mental Health Summary score for the population divided in quintiles based on their IDS or QIDS score.The QIDS-SR16 and QIDS-C16, as well as the longer 30-item versions, have highly acceptable psychometric properties and are treatment sensitive measures of symptom severity in depression.

Abstract

In the Texas Medication Algorithm Project (TMAP), patients were given algorithm-guided treatment (ALGO) or treatment as usual (TAU). The ALGO intervention included a clinical coordinator to assist the physicians and administer a patient and family education program. The primary comparison in the schizophrenia module of TMAP was between patients seen in clinics in which ALGO was used (n = 165) and patients seen in clinics in which no algorithms were used (n = 144). A third group of patients, seen in clinics using an algorithm for bipolar or major depressive disorder but not for schizophrenia, was also studied (n = 156). The ALGO group had modestly greater improvement in symptoms (Brief Psychiatric Rating Scale) during the first quarter of treatment. The TAU group caught up by the end of 12 months. Cognitive functions were more improved in ALGO than in TAU at 3 months, and this difference was greater at 9 months (the final cognitive assessment). In secondary comparisons of ALGO with the second TAU group, the greater improvement in cognitive functioning was again noted, but the initial symptom difference was not significant.

Abstract

The risk-to-benefit ratio of the use of unimodal antidepressants (ADs) as adjuncts to mood stabilizers continues to be an area of controversy and disagreement among experts in the field. This paper reviews new data on: (1) depression in bipolar illness, (2) switch rates on ADs and (3) risks of AD discontinuation that are pertinent to the ongoing discussion and recommendations.In the first study reviewed, 258 outpatients with bipolar illness were assessed prospectively on a daily basis using the National Institute of Mental Health-Life Chart Method (NIMH-LCM) for 1 year. In the second study, 127 bipolar depressed patients were randomized to 10 weeks of sertraline, bupropion, or venlafaxine, as adjuncts to mood stabilizers; non-responders were re-randomized and responders were offered a year of continuation treatment. In the final study, Altshuler et al. retrospectively and prospectively assessed the risk of depressive relapses in patients who remained on ADs after 2 months of euthymia compared with those who discontinued ADs.Despite intensive naturalistic treatment, the 258 outpatients with bipolar illness followed prospectively for 1 year showed three times as many days depressed as days manic, re-emphasizing the considerable depressive morbidity that remains in bipolar disorder despite the number of treatment options available. In the study of bipolar depressed patients randomized to one of three ADs, a range of severities and durations of hypomanic to manic switches were discerned following 175 trials of AD augmentation of treatment with a mood stabilizer. Of the acute 10-week trials, 9.1% were associated with switches into hypomania or mania and another 9.1% with a week or more of hypomania alone (with no to minimal dysfunction). In 73 continuation phase AD trials, 16.4 and 19.2% were similarly associated with hypomanic to manic and hypomanic switches, respectively. In the Altshuler et al. studies, those who remained well on any AD for more than 2 months (only 15-20% of those initially treated) and who continued on ADs showed a lesser rate of relapse into depression over 1 year (35 and 36% in the first and second study, respectively) compared with those who discontinued their ADs (68 and 70% relapsing into depression). Surprisingly, this continuation of ADs was associated with no increase in the rate of switching into mania compared with those stopping ADs.These data reveal that depression and depressive cycling remain a substantial problem in some two-thirds of intensively treated bipolar outpatients. Acute AD augmentation was associated with a modest response rate and 18.2% switched into a hypomanic to manic episode, and 35.6% of the continuation trials showed these two types of switches. Two separate studies suggest that in the very small subgroup who remain well on ADs for at least 2 months, one should consider continuation of this AD augmentation treatment, because AD discontinuation appears associated with a substantially increased risk of depression relapse over the subsequent year with no reduced risk of switching into mania.

Abstract

Selected recent findings of the Stanley Foundation Bipolar Network are briefly reviewed and their clinical implications discussed.Daily prospective ratings on the NIMH-LCM indicate a high degree of residual depressive morbidity (three times that of hypomania or mania) despite active psychopharmacological treatment with a variety of modalities including mood stabilizers, antidepressants, and benzodiazepines, as well as antipsychotics as necessary. The rates of switching into brief to full hypomania or mania during the use of antidepressants is described, and new data suggesting the potential utility of continuing antidepressants in the small group of patients showing an initial acute and persistent response is noted. Bipolar patients with a history of major environmental adversities in childhood have a more severe course of illness and an increased incidence of suicide attempts compared with those without. Preliminary open data suggest useful antidepressant effects of the atypical antipsychotic quetiapine, while a double-blind randomized controlled study failed to show efficacy of omega-3 fatty acids (6 g of eicosapentaenoic acid compared with placebo for 4 months) in the treatment of either acute depression or rapid cycling. The high prevalence of overweight and increased incidence of antithyroid antibodies in patients with bipolar illness is highlighted.Together, these findings suggest a very high degree of comorbidity and treatment resistance in outpatients with bipolar illness treated in academic settings and the need to develop not only new treatment approaches, but also much earlier illness recognition, diagnosis, and intervention in an attempt to reverse or prevent this illness burden.

Abstract

Although psychosis is common in bipolar disorder, few studies have examined the prognostic significance of psychotic features. In addition, some studies suggest that the presence of mood-incongruent psychosis, in particular, is associated with poorer outcome compared with mood-congruent psychosis. We assesses the phenomenology and prevalence of mood-congruent and mood-incongruent psychotic symptoms in 352 patients with bipolar I disorder participating in the Stanley Foundation Bipolar Treatment Network. We compared the demographic and clinical features, and measures of psychosocial and vocational functioning in patients with and without a history of psychosis. The phenomenology of psychosis in this cohort of patients with bipolar disorder was similar to that reported in earlier studies and supported the lack of diagnostic specificity of any one type of psychotic symptom. There were no significant differences between patients with and without a history of psychosis on any demographic, psychosocial, vocational, or course of illness variables. Only family history of bipolar disorder was significantly more common in patients with nonpsychotic bipolar disorder compared to patients with a history of psychosis. Among bipolar patients with a history of psychosis, only the proportion of women and lifetime prevalence rates of anxiety disorders occurred significantly more in patients with mood-incongruent delusions. In this large cohort of outpatients with bipolar I disorder, neither a history of psychosis nor of mood-incongruent psychosis had prognostic significance at entry into the Network. The lack of observable prognostic impact may have been, in part, due to the relatively high morbidity and poor functional outcome of a substantial portion of the total cohort.

Abstract

While guidelines for treating patients with bipolar depression recommend discontinuing antidepressants within 6 months after remission, few studies have assessed the implications of this strategy on the risk for depressive relapse. This study examined the effect of antidepressant discontinuation or continuation on depressive relapse risk among bipolar subjects successfully treated for an acute depressive episode.Eighty-four subjects with bipolar disorder who achieved remission from a depressive episode with the addition of an antidepressant to an ongoing mood stabilizer regimen were followed prospectively for 1 year. The risk of depressive relapse among 43 subjects who stopped antidepressant treatment within 6 months after remission ("discontinuation group") was compared with the risk among 41 subjects who continued taking antidepressants beyond 6 months ("continuation group").A Cox proportional hazards regression analysis indicated that shorter antidepressant exposure time following successful treatment was associated with a significantly shorter time to depressive relapse. Furthermore, patients who discontinued antidepressant treatment within the first 6 months after remission experienced a significantly shorter period of euthymia before depressive relapse over the length of 1-year follow-up. One year after successful antidepressant response, 70% of the antidepressant discontinuation group experienced a depressive relapse compared with 36% of the continuation group. By the 1-year follow-up evaluation, 15 (18%) of the 84 subjects had experienced a manic relapse; only six of these subjects were taking an antidepressant at the time of manic relapse.The risk of depressive relapse in patients with bipolar illness was significantly associated with discontinuing antidepressants soon after remission. The risk of manic relapse was not significantly associated with continuing use of antidepressant medication and, overall, was substantially less than the risk of depressive relapse. Maintenance of antidepressant treatment in combination with a mood stabilizer may be warranted in some patients with bipolar disorder.

Abstract

Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder. The authors report a 47-week comparison of olanzapine and divalproex.This 47-week, randomized, double-blind study compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed episodes of bipolar disorder (N=251). The only other psychoactive medication allowed was lorazepam for agitation. The primary efficacy instrument was the Young Mania Rating Scale; a priori protocol-defined threshold scores were > or =20 for inclusion, < or =12 for remission, and > or = 15 for relapse. Analytical techniques included mixed model repeated-measures analysis of variance for change from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and Kaplan-Meier estimates of time to events of interest.Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group. Median time to symptomatic mania remission was significantly shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness.In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ.

Abstract

A number of recent longitudinal outcome studies have found substantial long-term morbidity in patients with bipolar disorder. The detailed course and pattern of illness emerging despite comprehensive treatment with mood stabilizers and adjunctive agents have previously not been well delineated.258 consecutive outpatients admitted from 1996 to 1999 to the Stanley Foundation Bipolar Network who had a full year of prospective daily clinician ratings on the National Institute of Mental Health-Life Chart Method were included in the analysis. Patients were diagnosed by the Structured Clinical Interview for DSM-IV, with the majority (76%) having bipolar I disorder. They completed a questionnaire on demographics and prior illness course, and variables associated with outcome were examined in a hierarchical multinomial logistic regression analysis. Patients were treated naturalistically with a mean of 4.1 psychotropic medications during the year.Despite comprehensive pharmacologic treatment, mean time depressed (33.2% of the year) was 3-fold higher than time manic (10.8%); 62.8% of patients had 4 or more mood episodes per year. Two thirds of the patients were substantially impacted by their illness; 26.4% were ill for more than three fourths of the year, and 40.7% were intermittently ill with major affective episodes. After logistic regression analysis, those who were ill most of the year, compared with the largely well group, had a significantly greater family history of substance abuse, 10 or more depressive episodes, and limited occupational functioning prior to Network entry.A majority of outpatients with bipolar illness, even with intense monitoring and treatment in specialty clinics, have a considerable degree of residual illness-related morbidity, including a 3-fold greater amount of time spent depressed versus time spent manic. A personal or family history of substance abuse, 10 or more prior depressions, and limited occupational functioning predicted the poorest outcomes. Additional interventions, particularly those targeted at treating depressive phases of bipolar illness, are greatly needed.

Abstract

Clinical factors related to suicide and suicide attempts have been studied much more extensively in unipolar depression compared with bipolar disorder. We investigated demographic and course-of-illness variables to better understand the incidence and potential clinical correlates of serious suicide attempts in 648 outpatients with bipolar disorder.Patients with bipolar I or II disorder (DSM-IV criteria) diagnosed with structured interviews were evaluated using self-rated and clinician-rated questionnaires to assess incidence and correlates of serious suicide attempts prior to study entry. Clinician prospective ratings of illness severity were compared for patients with and without a history of suicide attempt.The 34% of patients with a history of suicide attempts, compared with those without such a history, had a greater positive family history of drug abuse and suicide (or attempts); a greater personal history of early traumatic stressors and more stressors both at illness onset and for the most recent episode; more hospitalizations for depression; a course of increasing severity of mania; more Axis I, II, and III comorbidities; and more time ill on prospective follow-up. In a hierarchical logistic regression, a history of sexual abuse, lack of confidant prior to illness onset, more prior hospitalizations for depression, suicidal thoughts when depressed, and cluster B personality disorder remained significantly associated with a serious suicide attempt.Our retrospective findings, supplemented by prospective follow-up, indicate that a history of suicide attempts is associated with a more difficult course of bipolar disorder and the occurrence of more psychosocial stressors at many different time domains. Greater attention to recognizing those at highest risk for suicide attempts and therapeutic efforts aimed at some of the correlates identified here could have an impact on bipolar illness-related morbidity and mortality.

Abstract

The prevalence of lifetime alcohol abuse and/or dependence (alcoholism) in patients with bipolar disorder has been reported to be higher than in all other axis I psychiatric diagnoses. This study examined gender-specific relationships between alcoholism and bipolar illness, which have previously received little systematic study.The prevalence of lifetime alcoholism in 267 outpatients enrolled in the Stanley Foundation Bipolar Network was evaluated by using the Structured Clinical Interview for DSM-IV. Alcoholism and its relationship to retrospectively assessed measures of the course of bipolar illness were evaluated by patient-rated and clinician-administered questionnaires.As in the general population, more men (49%, 57 of 116) than women with bipolar disorder (29%, 44 of 151) met the criteria for lifetime alcoholism. However, the risk of having alcoholism was greater for women with bipolar disorder (odds ratio=7.35) than for men with bipolar disorder (odds ratio=2.77), compared with the general population. Alcoholism was associated with a history of polysubstance use in women with bipolar disorder and with a family history of alcoholism in men with bipolar disorder.This study suggests that there are gender differences in the prevalence, risk, and clinical correlates of alcoholism in bipolar illness. Although this study is limited by the retrospective assessment of illness variables, the magnitude of these gender-specific differences is substantial and warrants further prospective study.

Abstract

Randomized controlled trials have demonstrated the efficacy of olanzapine for treating acute mania or depression symptoms in patients with bipolar disorder. We aimed to evaluate the effectiveness of this medication in more usual care outpatient settings. A consecutive series of 15 patients entered an open, uncontrolled 8-week trial of olanzapine monotherapy. Inclusion criteria included significant hypomanic or manic symptoms greater than or equal to 15 on the Young Mania Rating Scale and no psychotic symptoms. The majority of patients experienced significant decreases in mania ratings and more limited improvement on depression ratings. Most patients reported adverse events consistent with other studies, but few discontinued due to these complaints. This case series highlights the individual variation in response to a proven medication. Furthermore, it highlights that those medications effective at one end of the mood spectrum may not be equally or simultaneously effective with other symptoms, emphasizing the complexity of treating bipolar illness.

Abstract

The Texas Medication Algorithm Project (TMAP) assessed the clinical and economic impact of algorithm-driven treatment (ALGO) as compared with treatment-as-usual (TAU) in patients served in public mental health centers. This report presents clinical outcomes in patients with a history of mania (BD), including bipolar I and schizoaffective disorder, bipolar type, during 12 months of treatment beginning March 1998 and ending with the final active patient visit in April 2000.Patients were diagnosed with bipolar I disorder or schizoaffective disorder, bipolar type, according to DSM-IV criteria. ALGO was comprised of a medication algorithm and manual to guide treatment decisions. Physicians and clinical coordinators received training and expert consultation throughout the project. ALGO also provided a disorder-specific patient and family education package. TAU clinics had no exposure to the medication algorithms. Quarterly outcome evaluations were obtained by independent raters. Hierarchical linear modeling, based on a declining effects model, was used to assess clinical outcome of ALGO versus TAU.ALGO and TAU patients showed significant initial decreases in symptoms (p =.03 and p

Abstract

Medication treatment algorithms may improve clinical outcomes, uniformity of treatment, quality of care, and efficiency. However, such benefits have never been evaluated for patients with severe, persistent mental illnesses. This study compared clinical and economic outcomes of an algorithm-driven disease management program (ALGO) with treatment-as-usual (TAU) for adults with DSM-IV schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) treated in public mental health outpatient clinics in Texas.The disorder-specific intervention ALGO included a consensually derived and feasibility-tested medication algorithm, a patient/family educational program, ongoing physician training and consultation, a uniform medical documentation system with routine assessment of symptoms and side effects at each clinic visit to guide ALGO implementation, and prompting by on-site clinical coordinators. A total of 19 clinics from 7 local authorities were matched by authority and urban status, such that 4 clinics each offered ALGO for only 1 disorder (SCZ, BD, or MDD). The remaining 7 TAU clinics offered no ALGO and thus served as controls (TAUnonALGO). To determine if ALGO for one disorder impacted care for another disorder within the same clinic ("culture effect"), additional TAU subjects were selected from 4 of the ALGO clinics offering ALGO for another disorder (TAUinALGO). Patient entry occurred over 13 months, beginning March 1998 and concluding with the final active patient visit in April 2000. Research outcomes assessed at baseline and periodically for at least 1 year included (1) symptoms, (2) functioning, (3) cognitive functioning (for SCZ), (4) medication side effects, (5) patient satisfaction, (6) physician satisfaction, (7) quality of life, (8) frequency of contacts with criminal justice and state welfare system, (9) mental health and medical service utilization and cost, and (10) alcohol and substance abuse and supplemental substance use information. Analyses were based on hierarchical linear models designed to test for initial changes and growth in differences between ALGO and TAU patients over time in this matched clinic design.

Abstract

This study compares ratings obtained with an itemized, clinician-rated, symptom severity measure--the 24-item Brief Psychiatric Rating Scale (BPRS(24))--to a Physician Global Rating Scale (PhGRS), a Patient Global Rating Scale (PtGRS) and the clinician-completed Multnomah Community Ability Scale (MCAS) in patients with bipolar disorder (BPD). A total of 69 patients (25 inpatients and 44 outpatients) with BPD were enrolled in a feasibility study of the use of medication algorithms in the treatment of BPD. Clinicians at each visit completed the BPRS(24), PhGRS and MCAS, and patients completed the PtGRS. Analyses compared the BPRS(24) and BPRS subscales with the PtGRS, PhGRS and MCAS. PtGRS scores correlated poorly with BPRS(24) and with PhGRS scores at baseline, although PtGRS change scores correlated moderately with BPRS(24) change scores. Baseline BPRS(24) and PhGRS scores correlated moderately at baseline with somewhat stronger correlations found on change scores for the two measures. MCAS scores showed moderate correlations with BPRS(24) scores both at baseline and with change over time. Global assessments by patients or physicians only moderately or poorly reflected BPRS(24) scores. Itemized symptom measures to gauge severity of illness or change over time are preferred over patient or physician global judgments.

Abstract

To develop a statistic measuring the impact of algorithm-driven disease management programs on outcomes for patients with chronic mental illness that allowed for treatment-as-usual controls to "catch up" to early gains of treated patients.Statistical power was estimated from simulated samples representing effect sizes that grew, remained constant, or declined following an initial improvement. Estimates were based on the Texas Medication Algorithm Project on adult patients (age > or = 18) with bipolar disorder (n = 267) who received care between 1998 and 2000 at 1 of 11 clinics across Texas.Study patients were assessed at baseline and three-month follow-up for a minimum of one year. Program tracks were assigned by clinic.Hierarchical linear modeling was modified to account for declining-effects. Outcomes were based on 30-item Inventory for Depression Symptomatology-Clinician Version.Declining-effect analyses had significantly greater power detecting program differences than traditional growth models in constant and declining-effects cases. Bipolar patients with severe depressive symptoms in an algorithm-driven, disease management program reported fewer symptoms after three months, with treatment-as-usual controls "catching up" within one year.In addition to psychometric properties, data collection design, and power, investigators should consider how outcomes unfold over time when selecting an appropriate statistic to evaluate service interventions. Declining-effect analyses may be applicable to a wide range of treatment and intervention trials.

Abstract

Previously, we found an increased prevalence of thyroid autoantibodies in patients with bipolar disorder. In the present study, we investigated other signs of immune activation in bipolar patients, in particular an activation of the T cell system.Fluorescence activated cell scanning (FACS) analysis was performed on lymphocytes of 64 outpatients with DSM-IV bipolar disorder using the T cell marker CD3 in combination with the activation markers MHC-class II, CD25, CD69 or CD71. In 34 patients, these assays were repeated after an interval of 2 years. In addition, T cell activation was determined by measuring serum soluble IL-2 receptor (sIL-2R) in 172 bipolar outpatients. Outcomes were compared with a healthy control group.Significantly higher numbers of circulating activated T cells and raised sIL-2R levels were found in euthymic, manic, and depressed bipolar patients when compared with healthy controls. In general, these abnormalities were stable over time. Manic patients showed significantly higher levels of sIL-2R in comparison with depressed patients.The T cell system was found to be activated in both symptomatic and euthymic patients with bipolar disorder. The pathophysiological significance of these findings remains to be explored.

Review of the use of topiramate for treatment of bipolar disordersJOURNAL OF CLINICAL PSYCHOPHARMACOLOGYSuppes, T.2002; 22 (6): 599-609

Abstract

Lithium alone or in combination with other psychotherapeutic drugs has long been the gold standard of management for bipolar disorder (BD). Recognition of its limitations in the acute and chronic management of BD has led to the development of alternative therapies. One such approach involves the use of antiepileptic drugs (AEDs). The AED topiramate is currently being studied in the efficacy and management of BD. Topiramate has mechanisms in common with other AEDs, including sodium channel-blocking activity and enhancement of cerebral GABA concentrations. Open-label trials have evaluated topiramate at mean daily doses of 100 to 300 mg in various BD subtypes, including acute mania, depression, rapid-cycling, mixed states, and BD refractory to other medications. Results from these trials suggest topiramate may be efficacious in BD subtypes, particularly in rapid-cycling patients and those refractory to conventional treatment. Its side effect profile appears benign when used as monotherapy or in combination with other mood stabilizers. Placebo-controlled, double-blind studies are warranted to evaluate topiramate further in BD.

Abstract

The rate of lamotrigine-associated rash in patients with mood disorders has not been well characterized. The objective of this report was to determine rash rates in clinical trials of lamotrigine in DSM-IV unipolar depression or bipolar disorder.A retrospective analysis was conducted of rates of lamotrigine-related rash in 12 multicenter studies, including 1 open study, 7 randomized controlled acute trials, and 4 randomized controlled maintenance trials from 1996 to 2001.A total of 1955 patients were treated with lamotrigine in open-label settings (open-label phases preceding or following randomization and 1 stand-alone open-label study); 1198 patients received lamotrigine in controlled settings, and 1056 patients received placebo. In controlled settings, rates of benign rash were 8.3% and 6.4% in lamotrigine- and placebo-treated patients, respectively. Rates of serious rash were 0% with lamotrigine, 0.1% (N = 1) with placebo, and 0% with comparators. In the open-label setting, the overall rate of rash for lamotrigine was 13.1% (N = 257) and of serious rash, 0.1% (N = 2). One mild case of Stevens-Johnson syndrome not requiring hospitalization occurred in a patient treated with lamotrigine. There were no cases of toxic epidermal necrolysis in any setting.Serious drug eruptions associated with lamotrigine were rare. Although rash is a potentially life-threatening reaction, the risk of serious rash due to lamotrigine should be weighed against more common risks associated with untreated or undertreated bipolar depression.

Abstract

Anticonvulsants have provided major treatment advances for patients with bipolar disorder. Many of these drugs, including several with proven efficacy in bipolar mania or depression, enhance the activity of the gamma-amino butyric acid (GABA) neurotransmitter system. A new anticonvulsant, tiagabine, has selective GABAergic activity and is approved for patients with partial epilepsy. Few reports of its potential effectiveness in bipolar disorder, however, have been published. We sought to evaluate the effectiveness of tiagabine added to ongoing medication regimens in patients with bipolar disorder inadequately responsive to or intolerant of usual treatments.Seventeen treatment-refractory patients participating in the Stanley Foundation Bipolar Network (SFBN) long-term follow-up study were offered open treatment with add-on tiagabine after discussion of the risks, benefits, other treatment options and giving informed consent. Patients' clinical symptoms and somatic complaints were closely monitored with SFBN longitudinal and cross-sectional ratings. Four patients discontinued low-dose tiagabine prior to the second visit and were excluded from data analysis.Thirteen patients received a mean of 38 days of treatment at a mean dose of 8.7 mg/day of tiagabine. On the Clinical Global Impression Scale for Bipolar Disorder Overall category, three (23%) patients showed much or very much improvement and 10 (77%) patients showed no change or worsening. Three significant adverse events were noted, including two presumptive seizures.Open add-on tiagabine for treatment-refractory patients with bipolar disorder demonstrated limited efficacy with the majority of patients showing no change or worsening of clinical symptoms. In addition, patients experienced serious side-effects attributed as likely due to the medication, which resolved without lasting consequence when tiagabine was discontinued.

Abstract

This review was generated from discussions by the Pharmacologic and Somatic Treatments Section of the National Institute of Mental Health Strategic Plan for Mood Disorders Committee on advancing novel pharmacologic and somatic treatments for mood disorders. The opening section of the article summarizes in broad strokes, current pharmacologic treatments, and new directions in the field. Thereafter the topics focus on specific research initiatives that could advance the current therapeutics for mood disorders including new basic and clinical research in vivo human imaging procedures, somatic therapeutics, and the vast new area of pharmacogenetics. New scientific and technical opportunities exist today based on advances in basic neuroscience, opportunities in clinical testing, industry interest in advancing central nervous system therapeutics, and on active consumer advocacy groups. The question of how to bring all of these positive forces together to accelerate discovery in mood disorder thera-peutics is the topic of this article.

Abstract

Research has demonstrated that beliefs or expectancies can exert a powerful influence on treatment and/or drug effects. As patients participate in more complementary and/or alternative treatments for psychiatric conditions, it is important to assess the role of belief or expectancy on response to nontraditional treatment approaches. The Acupuncture Beliefs Scale was developed to assess belief in the efficacy of acupuncture for both physical and psychiatric symptoms and conditions. Development and psychometric properties of the scale are described.Research personnel solicited statements regarding the potential experience and effects of acupuncture. These items were collapsed into a set of 36 items, with some rotated to avoid response bias. Outpatients diagnosed with bipolar disorder and undergraduates completed the scale (n = 118).The scale yielded excellent internal consistency (coefficient alpha = 0.97), and item-total score correlations between 0.37 and 0.83. Principal component analysis with a varimax rotation revealed three significant and meaningful factors that were consistent across both subject groups. Factors appeared to capture general endorsement of acupuncture treatment, beliefs in the scientific value and credibility of acupuncture treatment, and beliefs about the procedures and physical experience of acupuncture.The Acupuncture Beliefs Scale is a 36-item self-report scale that may be useful for measurement of beliefs in the effectiveness of acupuncture treatment.

Abstract

The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial.A 3-week, randomized, double-blind trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms, respectively. Safety was assessed with several measures.The protocol defined baseline-to-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex (N=123). A priori categorizations defined response and remission rates: 54.4% of olanzapine-treated patients responded (> or = 50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale < or = 12), compared to 34.1% of divalproex-treated patients. The decrease in Hamilton depression scale score was similar in the two treatment groups. Completion rates for the 3-week study were similar in both groups. The most common treatment-emergent adverse events (incidence >10%) occurring more frequently during treatment with olanzapine were dry mouth, increased appetite, and somnolence. For divalproex, nausea was more frequently observed. The average weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex treatment.The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission, compared with the divalproex treatment group. Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex.

Abstract

The process and outcome of a consensus conference to develop revised algorithms for treatment of bipolar disorder to be implemented in the public mental health system of Texas are described. These medication algorithms for bipolar disorder are an update of those developed for the Texas Medication Algorithm Project, a research study that tested the clinical and economic impact of treatment guidelines for major psychiatric illnesses treated in the Texas public mental health system (Texas Department of Mental Health and Mental Retardation [TDMHMR]).Academic clinicians and researchers, practicing clinicians in the TDMHMR system, administrators, advocates, and consumers participated in a consensus conference in August 2000. Participants attended presentations reviewing new evidence in the pharmacologic treatment of bipolar disorder and discussed the needs of consumers in the TDMHMR system. Principles were enumerated, including balancing of evidence for efficacy, tolerability, and safety in medication choices. A set of 7 distinct algorithms was drafted. In the following months, a subcommittee condensed this product into 2 primary algorithms.The panel agreed to 2 primary algorithms: treatment of mania/hypomania, including 3 pathways for treatment of euphoric symptoms, mixed or dysphoric symptoms, and psychotic symptoms; and treatment of depressive symptoms. General principles to guide algorithm implementation were discussed and drafted.The revised algorithms are currently being disseminated and implemented within the Texas public mental health system. The goals of the Texas initiative include increasing the consistency of appropriate treatment of bipolar disorder, encouraging systematic and optimal use of available pharmacotherapies, and improving the outcomes of patients with bipolar disorder.

Abstract

Overweight and obesity are common clinical problems encountered in the treatment of bipolar disorder. We therefore assessed the prevalence and clinical correlates of overweight, obesity, and extreme obesity in 644 bipolar patients.644 outpatients with DSM-IV bipolar disorder in the Stanley Foundation Bipolar Treatment Outcomes Network were evaluated with structured diagnostic interviews and clinician- and self-administered questionnaires to determine bipolar disorder diagnoses, demographic and historical illness characteristics, comorbid Axis I diagnoses, medical histories, health habits, and body mass indices (BMMs).Fifty-eight percent of the patients with bipolar disorder were overweight, 21% were obese, and 5% were extremely obese. American patients had significantly higher mean (p < .0001) BMIs and significantly higher rates of obesity (p < .001) and extreme obesity (p < .001) than European patients. Significant associations (p < or = .001) were found between overweight, obesity. and extreme obesity and gender, age, income level, comorbid binge-eating disorder, hypertension, arthritis, diabetes mellitus, exercise habits, and coffee consumption. Current BMI and weight were each correlated with the number of weight gain-associated psychotropics to which patients had been exposed. Multinomial logistic regression (adjusted for site and eating disorder diagnosis and corrected for multiple comparisons) showed that (1) overweight was significantly associated with male gender and hypertension (p < .001), (2) obesity was significantly associated with hypertension (p < .001), and (3) extreme obesity was significantly associated with hypertension and arthritis (p < .001).Overweight, obesity, and extreme obesity were common in this group of bipolar patients, although it was unclear that their prevalence rates were truly elevated, because overweight and obesity are increasingly common public health problems among the general population. Correlates of overweight and obesity in bipolar disorder include patient and treatment variables such as gender, geographical location, comorbid binge-eating disorder, age, income level, degree of exposure to weight gain-associated psychotropics, medical disorders associated with obesity, and health habits.

Abstract

We assessed the prevalence of thyroperoxidase antibodies (TPO-Abs) and thyroid failure in outpatients with bipolar disorder compared with two control groups.The TPO-Abs of outpatients with DSM-IV bipolar disorder (n = 226), a population control group (n = 252), and psychiatric inpatients of any diagnosis (n = 3190) were measured. Thyroid failure was defined as a raised thyroid stimulating hormone level, previously diagnosed hypothyroidism, or both. Subjects were compared with attention to age, gender, and exposure to lithium.The TPO-Abs were more prevalent in bipolar patients (28%) than population and psychiatric controls (3-18%). The presence of TPO-Abs in bipolar patients was associated with thyroid failure, but not with age, gender, mood state, rapid cycling, or lithium exposure. Thyroid failure was present in 17% of bipolar patients and more prevalent in women. It was associated with lithium exposure, especially in the presence of TPO-Abs, but not with current rapid cycling, although an association may have been masked by thyroid hormone replacement.Thyroid autoimmunity was highly prevalent in this sample of outpatients with bipolar disorder and not associated with lithium treatment. These variables appear to be independent risk factors for the development of hypothyroidism, especially in women with bipolar disorder.

Abstract

There is growing awareness of the association between physical and sexual abuse and subsequent development of psychopathology, but little is known, however, about their relationship to the longitudinal course of bipolar disorder.We evaluated 631 outpatients with bipolar I or II disorder for general demographics, a history of physical or sexual abuse as a child or adolescent, course of illness variables, and prior suicide attempts, as well as SCID-derived Axis I and patient endorsed Axis II comorbidity.Those who endorsed a history of child or adolescent physical or sexual abuse, compared with those who did not, had a history of an earlier onset of bipolar illness, an increased number of Axis I, II, and III comorbid disorders, including drug and alcohol abuse, faster cycling frequencies, a higher rate of suicide attempts, and more psychosocial stressors occurring before the first and most recent affective episode. The retrospectively reported associations of early abuse with a more severe course of illness were validated prospectively.Greater appreciation of the association of early traumatic experiences and an adverse course of bipolar illness should lead to preventive and early intervention approaches that may lessen the associated risk of a poor outcome.

Abstract

Corticosteroids, such as prednisone and dexamethasone, are frequently prescribed medications sometimes associated with severe systemic side effects. Currently there are limited data regarding the psychiatric side effects of these medications, although mood changes and even psychoses have been reported. This study was designed to quantify psychiatric changes during brief courses of prednisone in patients with asthma. Outpatients with asthma (N = 32) receiving bursts of prednisone (>40 mg/day) were evaluated before, during, and after corticosteroid therapy by use of the Hamilton Rating Scale for Depression, the Young Mania Scale, the Brief Psychiatric Rating Scale, and the Internal State Scale. A Structured Clinical Interview for DSM-IV disorders was also conducted to examine past psychiatric history. Highly significant increases in the Young Mania Scale and Activation subscale of the Internal State Scale (both measures of mania) were observed with no increase in depression measures during the first 3 to 7 days of prednisone therapy. Mood changes were not correlated with improvement in airway obstruction, suggesting that mood elevations may not be in response to improvement in asthma symptoms. Subjects with past or current symptoms of depression had a significant decrease in depressive symptoms during prednisone therapy compared with those without depression. Some patients with posttraumatic stress disorder reported increases in depression and memories of the traumatic event during prednisone therapy. In summary, statistically significant changes in mood were observed even during brief courses of corticosteroids at modest dosages. The symptoms were primarily manic, not depressive. Persons with depression did not become more depressed during prednisone therapy, and, in fact, some showed improvement.

Abstract

Bipolar II disorder is a distinct, lifelong mental illness that affects at least 1.5 million people in the United States, is associated with a high incidence of comorbidity, and ends with completed suicide in 10% to 15% of diagnosed individuals. Bipolar II disorder is characterized by at least 1 major depressive episode with 1 or more hypomanic episodes, as opposed to manic or mixed episodes. While it is expected that there may be similarities in approaches to managing patients with bipolar I and bipolar II disorders, data suggest differential patient responses to pharmacologic treatments, supporting the need for research specifically in patients with bipolar II disorder. Despite the prevalence and severity of the disorder, a well-developed scientific database informing long-term treatment choices for bipolar II disorder as an illness differing from bipolar I disorder and major depressive disorder is virtually absent. A review of the limited and sometimes contradictory information stresses that more research is needed into prophylactic and maintenance treatment of bipolar II disorder.

Abstract

Since recent NIMH Bipolar Disorder Workshops highlighted the dearth of longitudinal and controlled studies of bipolar illness, the Stanley Foundation Bipolar Network (SFBN) has recruited a large cohort of patients with bipolar disorder to begin to address these issues. This report describes the demographics and course of illness characteristics of this study population.The first 261 outpatients to be diagnosed by the Structured Clinical Interview for DSM-IV (SCID) and complete a detailed patient and a brief clinician questionnaire are described. All patients met DSM-IV criteria for bipolar I (n=211), bipolar II (n=42), or NOS (n=5) or schizoaffective (n=3), bipolar type. Chi-square and t-tests were used to examine statistically significant associations among important demographic and descriptive items.The general demographic and illness characteristics were similar to those in many bipolar clinical samples and not dissimilar from those reported in epidemiological surveys. The majority of patients had been hospitalized, with almost half reporting a worsening of illness over time, and two-thirds were not asymptomatic between episodes. First treatment for patients had been delayed by an average of 10 years from illness onset (by SCID). Almost a third of patients had attempted suicide at least once, and 30% reported current suicidal ideation at study entry. A total of 62% reported moderate to severe impact of the illness on occupational functioning. Early onset bipolar illness (< or =17 years old) was associated with increased frequency of mood switches, worsening course of illness, and history of early abuse (physical, verbal, or sexual).The SFBN represents a sample of predominantly BP I patients largely recruited from the community who will be followed in detail longitudinally, participate in clinical trials, and thus help advance our understanding and treatment of this life-threatening medical disorder. While there is a broad range of illness characteristics and severity, the majority of patients have been severely impacted by their illness despite the availability of multiple conventional treatment approaches in the community. These data further underscore the need for development of new and earlier treatment interventions.The SFBN population is limited by the lack of random selection and represents a cohort willing to be treated and followed intensively in academic tertiary referral centers. While its characteristics are similar to many clinical study populations, the generalizability to non-clinic populations remains uncertain.

Abstract

The NIMH-Stanley Foundation Bipolar Treatment Outcome Network, a multisite clinical trials network, has been established to address many of the neglected areas of research in bipolar illness. The Network was designed so that it would be able to conduct randomized clinical trials at several different levels of methodologic rigor (blinded and open-label) both in academic and community practice settings in order to better assess long-term efficacy of existing treatments and develop new ones. In this fashion, large numbers of representative patients with bipolar disorder have been enrolled with an additional focus of elucidating possible clinical and biological predictors of treatment response. The unique focus of the Network is its systematic longitudinal approach to illness so that patients can be assessed comprehensively over the long-term in sequential randomized clinical trials at critical clinical decision points where data on relative efficacy are inadequate. Bipolar I and bipolar II patients with a range of illness variants and comorbidities are included. Daily prospective ratings of severity of mania and depression and associated degree of functional impairment are completed on the NIMH-Life Chart Method and a modified Clinical Global Impressions Scale for Bipolar Illness (CGI-BP) is utilized. More detailed cross-sectional ratings for depression (Inventory of Depressive Symptomatology), mania (Young Mania Rating Scale), and psychosis (Positive and Negative Syndrome Scale) are additionally used at academic centers. This article describes the rationale for the Network, its guiding principles, methods, and study design to systematically assess the highly variable course of bipolar illness and its response to current and future treatments.

Abstract

Bipolar patients with breakthrough major depressive episodes despite ongoing adequately-dosed mood stabilizer medication were randomized in a double-blind manner to one of three antidepressants with different mechanisms of action: bupropion, sertraline, or venlafaxine. Preliminary data are presented on the switch rates into hypomania or mania for the antidepressants as a group prior to unblinding the specific individual drug efficacy and tolerability data in this ongoing clinical trial.Subjects included 64 bipolar patients who participated at five sites in a 10-week double-blind trial for depression and a 1-year blinded continuation maintenance phase for responders. Nonresponders were re-randomized such that there were 95 acute treatment phases. In the acute phase, doses were titrated to clinical response, side effects, or maximum dose of bupropion (450 mg/day), sertraline (200 mg/day), or venlafaxine (375 mg/day). Daily ratings on the National Institute of Mental Health-Life Chart Methodology (NIMH-LCM) were inspected for the degree of improvement on the Clinical Global Impressions scale as revised for bipolar illness (CGI-BP) and the occurrence of hypomania or mania.Thirty-five (37%) of the 95 acute treatment phases were associated with a much or very much improved rating in depression on the CGI-BP. Thirteen (14%) of these 95 acute trials of antidepressants as adjuncts to mood stabilizers were associated with switches, seven into hypomania and six into mania. Forty-two patients elected to go into the continuation phase in 48 instances. Sixteen (33%) of the continuation phase trials were associated with mood switches, 10 into hypomania and six into mania.In this randomized double-blind prospective study of three second-generation antidepressants (bupropion, sertraline, and venlafaxine) in bipolar patients whose depression broke through ongoing treatment with mood stabilizers, switches into hypomania or mania occurred in 14% of the acute phases and 33% of the continuation phases. Individual data on each drug will be assessed in the next phase of the study after more subjects are recruited and the blind is broken.

Abstract

Bipolar disorder is a common, severe and cyclic psychiatric illness. A strong association between alcohol dependence and bipolar disorder has been reported in numerous studies. The abuse of other drugs including cocaine, amphetamines, opiates, cannabis, and prescription medications in bipolar patients is also an important public health concern and has been less extensively investigated. This review examines the abuse of drugs other than alcohol or nicotine in people with bipolar disorder. The high rates of milder affective symptoms but not mania observed in patients in drug abuse treatment settings suggests the symptoms may in many cases be associated with the drug use. However, such patients presenting in psychiatric settings might be suffering from cyclothymic and related attenuated bipolar disorders (type II). Substance abuse may be associated with medication non-compliance, more mixed or dysphoric mania and possibly an earlier onset of affective symptoms and more hospitalizations. The pharmacotherapy of patients with bipolar disorder and drug abuse is examined, including evidence on the use of mood stabilizers, neuroleptics and the newer atypical antipsychotics in this population.

Abstract

The Stanley Foundation Bipolar Network (SFBN) was created to address the paucity of help studies in bipolar illness.To describe the rationale and methods of the SFBN.The SFBN includes five core sites and a number of affiliated sites that have adopted consistent methodology for continuous longitudinal monitoring of patients. Open and controlled studies are performed as patients' symptomatology dictates.The reliability of SFBN raters and the validity of the rating instruments have been established. More than 500 patients are in continuous daily longitudinal follow-up. More than 125 have been randomised to one of three of the newer antidepressants (bupropion, sertraline and venlafaxine) as adjuncts in a study of mood stabilizers and 93 to omega-3 fatty acids. A number of open clinical case series have been published.Well-characterised patients are followed in a detailed continuous longitudinal fashion in both opportunistic case series and double-blind, randomised controlled trials with reliable and validated measures.

Abstract

The Stanley Foundation Bipolar Network (SFBN) evaluates treatments, course and clinical and neurobiological markers of response in bipolar illness.To give a preliminary summary of emerging findings in these areas.Studies with established and potentially antimanic, antidepressant and mood-stabilising agents range from open case series to double-blind randomised clinical trials, and use the same core assessment methodology, thereby optimising the comparability of the outcomes. The National Institute of Mental Health Life Chart Method is the core instrument for retrospective and prospective longitudinal illness description.The first groups of patients enrolled show a considerable degree of past and present symptomatology, psychiatric comorbidity and functional impairment. There are associations of both genetic and early environmental factors with more severe courses of illness. Open case series with add-on olanzapine, lamotrigine, gabapentin or topiramate show a differential spectrum of effectiveness in refractory patients.The SFBN provides important new data for the understanding and treatment of bipolar disorder.

Abstract

Use of treatment guidelines for treatment of major psychiatric illnesses has increased in recent years. The Texas Medication Algorithm Project (TMAP) was developed to study the feasibility and process of developing and implementing guidelines for bipolar disorder, major depressive disorder, and schizophrenia in the public mental health system of Texas. This article describes the consensus process used to develop the first set of TMAP algorithms for the Bipolar Disorder Module (Phase 1) and the trial testing the feasibility of their implementation in inpatient and outpatient psychiatric settings across Texas (Phase 2).The feasibility trial answered core questions regarding implementation of treatment guidelines for bipolar disorder. A total of 69 patients were treated with the original algorithms for bipolar disorder developed in Phase 1 of TMAP.Results support that physicians accepted the guidelines, followed recommendations to see patients at certain intervals, and utilized sequenced treatment steps differentially over the course of treatment. While improvements in clinical symptoms (24-item Brief Psychiatric Rating Scale) were observed over the course of enrollment in the trial, these conclusions are limited by the fact that physician volunteers were utilized for both treatment and ratings. and there was no control group.Results from Phases 1 and 2 indicate that it is possible to develop and implement a treatment guideline for patients with a history of mania in public mental health clinics in Texas. TMAP Phase 3, a recently completed larger and controlled trial assessing the clinical and economic impact of treatment guidelines and patient and family education in the public mental health system of Texas, improves upon this methodology.

Abstract

Bipolar disorder often co-occurs with other axis I disorders, but little is known about the relationships between the clinical features of bipolar illness and these comorbid conditions. Therefore, the authors assessed comorbid lifetime and current axis I disorders in 288 patients with bipolar disorder and the relationships of these comorbid disorders to selected demographic and historical illness variables.They evaluated 288 outpatients with bipolar I or II disorder, using structured diagnostic interviews and clinician-administered and self-rated questionnaires to determine the diagnosis of bipolar disorder, comorbid axis I disorder diagnoses, and demographic and historical illness characteristics.One hundred eighty-seven (65%) of the patients with bipolar disorder also met DSM-IV criteria for at least one comorbid lifetime axis I disorder. More patients had comorbid anxiety disorders (N=78, 42%) and substance use disorders (N=78, 42%) than had eating disorders (N=9, 5%). There were no differences in comorbidity between patients with bipolar I and bipolar II disorder. Both lifetime axis I comorbidity and current axis I comorbidity were associated with earlier age at onset of affective symptoms and syndromal bipolar disorder. Current axis I comorbidity was associated with a history of development of both cycle acceleration and more severe episodes over time.Patients with bipolar disorder often have comorbid anxiety, substance use, and, to a lesser extent, eating disorders. Moreover, axis I comorbidity, especially current comorbidity, may be associated with an earlier age at onset and worsening course of bipolar illness. Further research into the prognostic and treatment response implications of axis I comorbidity in bipolar disorder is important and is in progress.

Abstract

Patients with serious psychiatric disorders are frequently treated by primary care physicians, who may have difficulty keeping up with recent advances in psychiatry. This paper presents an updated synopsis for three major psychiatric illnesses: major depression, bipolar disorder, and schizophrenia. Current definitions, updated diagnostic criteria, short- and long-term treatment strategies with algorithms, and special challenges for the clinician are discussed for each of these illnesses. On the basis of each illness's distinct characteristics, five treatment principles are emphasized: 1) Treatment strategies should be long-term and should emphasize adherence, 2) treatment choice should be empirical, 3) combinations of medications may be helpful, 4) a combination of psychosocial and pharmacologic treatments may be more useful than either alone, and 5) the family or "significant others" as well as a consumer organization need to be involved. Some of the new directions in dinical research to refine these strategies and meet these challenges are also described.

Abstract

The phenomenon of frequent cycling in bipolar disorder was first recognized by Emil Kraepelin in 1913. More recently, rapid cycling has been reported to be a predictor of nonresponse to treatment. At the time of presentation, most patients with DSM-IV-defined rapid cycling appear to be in the depressed phase of their illness. Frequent and more severe episodes of depression appear to be the hallmark of rapid cycling. Reported in this article are recent preliminary data suggesting that the combination of lithium and divalproex sodium administered continuously over 6 months appears to result in marked acute and continuation antimanic efficacy in 85% of patients and marked antidepressant efficacy in 60%. However, only one half of patients experienced bimodal stabilization. Comorbid alcohol, cannabis, and/or cocaine abuse and/or dependence did not appear to directly affect the spectrum of efficacy of lithium and divalproex or response rates in compliant patients. Comorbidity appeared to alter prognosis by increasing the prevalence of poor compliance. The majority of patients receiving lithium and divalproex who required additional treatment were depressed, suggesting that the frequent recurrence of depression is the primary unmet need in patients with rapid cycling. The use of antidepressants in this population has been discouraged because of concerns about the possibility of cycle acceleration. There exists a need for a pharmacotherapy that not only possesses marked acute antidepressant properties, but that does so without inducing switching or cycle acceleration. A double-blind, placebo-controlled trial of lamotrigine monotherapy in bipolar I depression has demonstrated efficacy without causing switching at a rate exceeding placebo; however, this initial study excluded patients with rapid cycling. To explore the efficacy of lamotrigine in rapid cycling, a recent multicenter study has examined lamotrigine as a maintenance therapy for this population. The results indicate that lamotrigine may be a useful treatment for patients with rapid-cycling bipolar II disorder and that this drug has begun to address this unmet need.

Abstract

Patients with rapid-cycling bipolar disorder are often treatment refractory. This study examined lamotrigine as maintenance monotherapy for rapid-cycling bipolar disorder.Lamotrigine was added to patients' current psychotropic regimens and titrated to clinical effect during an open-label treatment phase. Stabilized patients were tapered off other psychotropics and randomly assigned to lamotrigine or placebo monotherapy for 6 months. Time to additional pharmacotherapy for emerging symptoms was the primary outcome measure. Secondary efficacy measures included survival in study (time to any premature discontinuation), percentage of patients stable without relapse for 6 months, and changes in the Global Assessment Scale and Clinical Global Impressions-Severity scale. Safety was assessed from adverse event, physical examination, and laboratory data.324 patients with rapid-cycling bipolar disorder (DSM-IV criteria) received open-label lamotrigine, and 182 patients were randomly assigned to the double-blind maintenance phase. The difference between the treatment groups in time to additional pharmacotherapy did not achieve statistical significance in the overall efficacy population. However, survival in study was statistically different between the treatment groups (p = .036). Analyses also indicated a 6-week difference in median survival time favoring lamotrigine. Forty-one percent of lamotrigine patients versus 26% of placebo patients (p = .03) were stable without relapse for 6 months of monotherapy. Lamotrigine was well tolerated; there were no treatment-related changes in laboratory parameters, vital signs, or body weight. No serious rashes occurred.This was the largest and only prospective placebo-controlled study of rapid-cycling bipolar disorder patients to date; results indicate lamotrigine monotherapy is a useful treatment for some patients with rapid-cycling bipolar disorder.

Abstract

Systematic and accurate depiction of a patient's course of illness is crucial for assessing the efficacy of maintenance treatments for bipolar disorder. This need to rate the long-term prospective course of illness led to the development of the National Institute of Mental Health prospective Life Chart Methodology (NIMH-LCM-p or LCM). The NIMH-LCM-p allows for the daily assessment of mood and episode severity based on the degree of mood associated functional impairment. We have previously presented preliminary evidence of the reliability and validity of the LCM, and its utility in clinical trials. This study is a further and more extensive validation of the clinician rated NIMH-LCM-p.Subjects included 270 bipolar patients from the five sites participating in the Stanley Foundation Bipolar Network. Daily prospective LCM ratings on the clinician form were initiated upon entry, in addition to at least monthly ratings with the Inventory of Depressive Symptomatology-clinician rated (IDS-C), the Young Mania Rating Scale (YMRS) and the Global Assessment of Functioning (GAF). We correlated appropriate measures and time domains of the LCM with the IDS-C, YMRS and GAF.Severity of depression on the LCM and on the IDS-C were highly correlated in 270 patients (r = -0.785, P < 0.001). Similarly, a strong correlation was found between LCM mania and the YMRS (r = 0.656, P < 0.001) and between the LCM average severity of illness and the GAF (r = -0.732, P < 0.001).These data further demonstrate the validity and potential utility of the NIMH-LCM-p for the detailed daily longitudinal assessment of manic and depressive severity and course, and response to treatment.

Abstract

Schizoaffective disorder is a common, severe, and lifelong illness; however, little is known about the pharmacologic treatment of this mental disorder. Divalproex has proven efficacy in the treatment of bipolar disorder. Therefore, to determine whether divalproex is also effective as adjunctive therapy for schizoaffective disorder, the authors performed a retrospective study of 20 patients in the public mental health system with schizoaffective disorder, bipolar type, who initiated divalproex therapy. The mean maximum dose of divalproex (+/-1 SD) was 1,150 mg (+/-400 mg; range, 500-2,000). The mean peak serum valproic acid level was 61 microg/mL (+/-25 microg/mL; range, 20-92). The overall improvement in Clinical Global Impression Scale scores was observed in 75% (15/20) of the patients (p = 0.0001). None in the sample worsened, and none discontinued divalproex because of side effects. These data suggest that divalproex is well-tolerated and effective as treatment of persistent schizoaffective disorder, bipolar type. Thus, divalproex may be an effective agent in the treatment of schizoaffective disorder as well as bipolar disorder. Controlled prospective trials in patients with schizoaffective disorder are needed to verify these findings.

Abstract

The McLean-Harvard First-Episode Project recruited affective and nonaffective patients at their first lifetime psychiatric hospitalization.Baseline evaluation and 6-month follow-up in 257 cases yielded recovery outcomes defined by syndromal (absence of DSM-IV criteria for a current episode) and functional (vocational and residential status at least at baseline levels) status. Time to recovery was assessed by survival analysis, and risk factors by multivariate logistic regression.Syndromal recovery was attained by 77% of cases over an average of 84 days. By diagnostic group, syndromal recovery rates ranked (p = .001) major affective disorders (81%) > nonaffective acute psychoses (74%) > schizoaffective disorders (70%) > schizophrenia (36%). Functional recovery was significantly associated to syndromal recovery, diagnosis, shorter hospitalization normalized to year, and older age at onset. Average hospital stay declined across the study period, but recovery did not vary with year of entry.Syndromal recovery was achieved by nearly one half of patients within 3 months of a first lifetime hospitalization for a psychotic illness, but functional recovery was not achieved by 6 months in nearly two thirds of patients who had attained syndromal recovery.

Abstract

One important aim of the recent reorganization of the National Institute of Mental Health (NIMH) is to streamline the development of new treatments for patients with severe mental illnesses, such as bipolar disorder. Researching new treatments for patients with bipolar disorder presents specific problems not readily addressed by traditional efficacy trial methodologies that aim to maximize internal validity. This article reexamines several assumptions that have guided the design of these efficacy trials but that also create obstacles for studies of bipolar disorder and suggests potential solutions. This article draws on literature from neurology and psychiatry and discussions at a MacArthur Foundation-sponsored Conference on Longitudinal Methodology in 1992 (David J. Kupfer, M.D., Chair), which brought together investigators to consider alternative designs for patients with severe and persistent mental illness. In addition, we benefited from discussions at two NIMH-sponsored conferences, one held in 1989 (Prien and Potter 1990) and the other in 1994 (Prien and Rush 1996), at which investigators and methodologists discussed issues surrounding the development and conduct of informative efficacy trials for patients with bipolar disorder. Based on these discussions and recent literature reviews, we 1) outline common problems in the development and evaluation of effective acute treatments for bipolar disorder and 2) suggest possible solutions to these impediments. We also discuss alternative designs by which to build a sequence of acute treatment studies from which efficacy, safety, and the comparative value of different treatments can be established.

Abstract

This review considers the evidence supporting the use of somatic therapies (medications and electroconvulsive therapy) in the treatment of acute mania associated with bipolar disorder. Data from randomized, controlled clinical trials have established the efficacy of lithium, divalproex sodium, and carbamazepine in the treatment of acute mania. The use of combinations of mood stabilizers in the treatment of acute mania has not been well examined in controlled trials. Conventional antipsychotics and some atypical antipsychotics are frequently used as initial or adjunctive treatment. Similarly, benzodiazepines are frequently used as adjunctive agents. Preliminary data suggest that some calcium channel blockers and several anticonvulsants, e.g., lamotrigine, gabapentin, and topiramate, may have therapeutic value in the treatment of acute mania. In contrast, electroconvulsive therapy is generally accepted as being highly effective despite the lack of controlled evidence.

Abstract

To preliminarily explore the spectrum of effectiveness and tolerability of the new antiepileptic drug topiramate in bipolar disorder, we evaluated the response of 56 bipolar outpatients in the Stanley Foundation Bipolar Outcome Network (SFBN) who had been treated with adjunctive topiramate in an open-label, naturalistic fashion.In this case series, response to topiramate was assessed every 2 weeks for the first 3 months according to standard ratings in the SFBN, and monthly thereafter while patients remained on topiramate. Patients' weights, body mass indices (BMIs), and side effects were also assessed.Of the 54 patients who completed at least 2 weeks of open-label, add-on topiramate treatment, 30 had manic, mixed, or cycling symptoms, 11 had depressed symptoms, and 13 were relatively euthymic at the time topiramate was begun. Patients who had been initially treated for manic symptoms displayed significant reductions in standard ratings scores after 4 weeks, after 10 weeks, and at the last evaluation. Those patients who were initially depressed or treated while euthymic showed no significant changes. Patients as a group displayed significant decreases in weight and BMI from topiramate initiation to week 4, to week 10, and to the last evaluation. The most common adverse side effects were neurologic and gastrointestinal.These preliminary open observations of adjunctive topiramate treatment suggest that it may have antimanic or anticycling effects in some patients with bipolar disorder, and may be associated with appetite suppression and weight loss that is often viewed as beneficial by the patient and clinician. Controlled studies of topiramate's acute and long-term efficacy and side effects in bipolar disorder appear warranted.

Abstract

To develop effect sizes for 3 mood stabilizers--lithium, divalproex sodium, and carbamazepine--for the acute-phase treatment of bipolar I or II disorder, mixed or manic episode, in children and adolescents aged 8 to 18 years.Forty-two outpatients with a mean age of 11.4 years (20 with bipolar I disorder and 22 with bipolar II disorder) were randomly assigned to 6 weeks of open treatment with either lithium, divalproex sodium, or carbamazepine. The primary efficacy measures were the weekly Clinical Global Impression Improvement scores and the Young Mania Rating Scale (Y-MRS).Using a > or = 50% change from baseline to exit in the Y-MRS scores to define response, the effect size was 1.63 for divalproex sodium, 1.06 for lithium, and 1.00 for carbamazepine. Using this same response measure with the intent-to-treat sample, the response rates were as follows: sodium divalproex, 53%; lithium, 38%; and carbamazepine, 38% (chi 2(2) = 0.85, p = .60). All 3 mood stabilizers were well tolerated, and no serious adverse effects were seen.Divalproex sodium, lithium, and carbamazepine all showed a large effect size in the open treatment of children and adolescents with bipolar I or II disorder in a mixed or manic episode.

Abstract

Mood symptoms are reported frequently in asthma patients, particularly during corticosteroid therapy. This investigation compared the Internal State Scale (ISS), a self-report measure of symptoms of mania and depression, to the Hamilton Rating Scale for Depression (HRSD), Young Mania Rating Scale (YMRS), and Brief Psychiatric Rating Scale (BPRS) in a group of asthma patients (n=60 at baseline) before, during, and after a 1-2 week burst of prednisone. The depression and well being subscales of the ISS correlated well with HDRS scores. The perceived conflict subscale correlated with the BPRS scores. However, none of the ISS subscales correlated consistently and specifically with the YMRS in this population. Possible explanations for differences observed in bipolar versus asthma patients given the ISS are discussed. These data suggest the ISS may be a useful tool for depression symptoms and overall psychopathology in asthma patients and in patients receiving corticosteroid therapy. However, its ability may be attenuated outside of the population for which it was designed.

Abstract

1. Some reports have suggested an increase in symptoms when switching patients with psychosis from clozapine to other atypical antipsychotics. 2. No data are available on switching between atypical antipsychotics other than clozapine, though this is common in clinical practice. 3. Six patients with schizophrenia or schizoaffective disorder, bipolar type were switched to quetiapine after finishing a clinical trial of sertindole. 4. During the observation period of two to ten weeks no subjects worsened and one improved. Side effects were mild. 5. These preliminary data suggest that switching between some atypical agents may be well tolerated. Larger controlled trials are needed to confirm this observation.

Abstract

Psychotic affective disorders are the most prevalent idiopathic psychoses, but their outcome from onset has rarely been studied. In this study, the authors determined the rate and latency of syndromal recovery and rates of functional recovery after first lifetime hospitalization in patients with first-episode psychotic affective disorders.From first lifetime hospitalization in 1989-1996, 219 patients with a DSM-IV psychotic affective illness were assessed at intervals over 24 months. Time to syndromal recovery (no longer meeting DSM-IV episode criteria) was assessed by survival analysis, and functional recovery (regaining baseline vocational and residential status) was rated. Factors associated with recovery were identified by bivariate and multivariate methods.By 3, 6, 12, and 24 months after first hospitalization, syndromal recovery was attained by 65.1%, 83.7%, 91.1%, and 97.5%, respectively, of subjects. Time to syndromal recovery (6.1 weeks to 50% of subjects recovered) was shorter for patients who had bipolar disorder, were married, were age 30 or older at onset, lacked comorbidity, required relatively brief hospitalization, and received fewer medicines. Functional recovery by 6 (30.4%) and 24 months (37. 6% of patients) was 2.6-2.7 times less likely than syndromal recovery; 63.1% of those recovering syndromally did not recover functionally by 2 years. Functional recovery was associated with older age at onset and shorter hospitalization. Annual recovery rates remained stable as mean hospital length of stay decreased 3. 6-fold over the 8-year study period.Syndromal recovery was attained by most psychotic affective disorder patients soon after hospitalization, but only one-third recovered functionally by 24 months. The findings suggest that these very common psychotic illnesses can carry a grave functional prognosis from the initial episode and first hospitalization.

Abstract

Course of illness is central to our focus on bipolar disorder due to the lifelong nature of this illness in the majority of patients. In this overview, we highlight areas of consensus and debate on factors that impact course of illness. Findings on age at onset, psychiatric comorbidity, frequency of episodes, cycle pattern, rapid cycling, mixed symptoms, and precipitants of episodes including use of substances and antidepressants and lithium discontinuation are discussed. The diversity and range of presentation and even course of illness become quickly apparent in this review. Highlighting these factors rather than seeking a unifying theory should be a productive way to refine our ability to identify additive factors contributing to course of illness for patients with bipolar disorder.

Abstract

Gabapentin, a new anti-epileptic agent, has been anecdotally reported to be effective in the treatment of mania. We systematically assessed the response rate in bipolar patients being treated adjunctively with gabapentin for manic symptoms, depressive symptoms, or rapid cycling not responsive to standard treatments.Twenty-eight bipolar patients experiencing manic (n = 18), depressive (n = 5), or rapid-cycling (n = 5) symptoms inadequately responsive to at least one mood stabilizer were treated in an open fashion with adjunctive gabapentin. Illness response was assessed using the Clinical Global Impression Scale modified for bipolar disorder (CGI-BP). A 'positive response' was operationalized as a CGI response of much or very much improved.Fourteen of the 18 (78%) treated for hypomania or mania had a positive response to a dosage range of 600-3,600 mg/day. Patients with hypomania responded fastest, with a positive response achieved in 12.7 +/- 7.2 days. Patients with classic mania had a mean time to positive response of 25 +/- 12 days, and in patients with mixed mania it was 31.8 +/- 20.9 days. All of the five patients treated for depression had a positive response within 21 +/- 13.9 days. Only one of five patients with rapid cycling had a positive response. Gabapentin was well tolerated by all patients, with the most common side-effect being sedation.Gabapentin appears to have acute anti-manic and anti-depressant properties as an adjunctive agent for refractory bipolar illness. Prospective double-blind studies are needed to further delineate its acute efficacy when used as monotherapy and its prophylactic efficacy as monotherapy or in conjuction with other mood stabilizers.

Abstract

Case series and follow-up studies suggest that clozapine may have mood-stabilizing properties in addition to antipsychotic action in patients with schizoaffective disorder, bipolar type, and bipolar I disorder, but the generalizability of these findings is limited. This article describes a randomized, open study of clozapine add-on therapy versus treatment as usual for patients with treatment-resistant illness and a history of mania.Thirty-eight patients meeting the DSM-IV criteria for schizoaffective or bipolar disorder that was deemed treatment-resistant were randomly assigned to clozapine add-on treatment (N = 19) or treatment as usual (no clozapine) (N = 19) and followed up for 1 year. Patients received monthly ratings on the Brief Psychiatric Rating Scale, Clinical Global Impression scale, Bech-Rafaelsen Mania Scale, Hamilton Depression Rating Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Abnormal Involuntary Movement Scale, and a 40-item side effect checklist. Differences between treatment groups were assessed according to a pattern-mix random-regression model. An additional analysis compared group differences in rating scale scores against relative time in the study.Significant between-group differences were found in scores on all rating scales except the Hamilton depression scale. Total medication use over 1 year significantly decreased in the clozapine group. No significant differences between groups in somatic complaints were noted. The subjects with nonpsychotic bipolar I disorder who received clozapine showed a degree of improvement similar to that of the entire clozapine-treated group. Clozapine dose was significantly higher for the patients with schizoaffective illness than for those with bipolar disorder.The results of this study support clozapine's independent mood-stabilizing property. They demonstrate that clozapine use was associated with significant clinical improvement relative to treatment as usual.

Abstract

Several case reports and open studies have reported the efficacy of lamotrigine in bipolar depression. A randomised placebo-controlled 7-week study comparing two doses of lamotrigine with placebo in 195 patients with moderate to severe bipolar depression has now been completed. Lamotrigine was superior to placebo after 3 weeks as assessed by changes in the Montgomery-Asberg Depression Rating Scale (MADRS). A response, defined as more than 50% improvement on the MADRS occurred in 56 and 48% of the lamotrigine 200 and 50 mg/day groups, respectively, compared with 29% for placebo (P<0.05). There was no evidence that lamotrigine destabilised mood or precipitated mania. Tolerability was good and there were no cases of serious rashes. Preliminary results from an ongoing study also indicate that lamotrigine is more effective than gabapentin in bipolar depression. In conclusion, lamotrigine is effective in alleviating bipolar depression, without causing mood destabilisation. Slow dosage escalation yields good tolerability.

Abstract

This article provides an overview of the issues involved in developing, using, and evaluating specific medication guidelines for patients with psychiatric disorders. The potential advantages and disadvantages, as well as the essential elements in the structure of algorithms, are illustrated by experience to date with the Texas Medication Algorithm Project, a public-academic collaboration. Phase 1 entailed assembling research findings on the efficacy of medications for schizophrenic, bipolar, and major depressive disorders. This knowledge was evaluated for its quality and relevance, integrated with expert clinical judgment as well as input by practicing clinicians, family advocates, and patients. Phase 1 (the design and development of the algorithms) was followed by a feasibility test (Phase 2). Phase 3 is an ongoing evaluation comparing the clinical and economic effects of using specific medication guidelines (algorithms) versus treatment as usual in public sector patients with severe and persistent mental illnesses.

Abstract

Recently, a number of new agents have become available to treat bipolar disorder, however many patients may not respond fully even when used in combination. Early reports in epilepsy studies suggested mood-related effects of lamotrigine treatment, as have preliminary reports in bipolar patients.Seventeen patients meeting DSM-IV criteria for bipolar I (n = 9) or bipolar II (n = 8) disorder displaying affective symptoms and a past history of inadequate response or tolerability to at least two standard mood stabilizing agents were recruited through the Stanley Foundation Bipolar Network and treated with the new anticonvulsant lamotrigine in an add-on, open-label study. Response to therapy was assessed using the Clinical Global Impression Scale modified for bipolar disorder.The mean dose of lamotrigine was 187+/-157 mg/day (range 50-600 mg/day) for a mean duration of 159+/-109 days (range 14-455 days). Eleven (65%) patients were rated as very much or much improved. Lamotrigine was well tolerated, and may have mood stabilizing and antidepressant properties in some patients with bipolar disorder.The study is hypothesis generating because it was uncontrolled and open. Controlled studies are warranted.This preliminary report supports clinical improvement for both mood cycling and depression in patients with bipolar disorder treated with lamotrigine.

Abstract

Medication treatment algorithms have been suggested as a strategy to provide uniform care at predictable costs. The Texas Medication Algorithm Project is a 3-phase study designed to provide solid data on the usefulness of medication algorithms. In phase 1, medication algorithms for the treatment of schizophrenia, major depressive disorder, and bipolar disorder were developed. Phase 2 was a feasibility study of these algorithms, and phase 3, now underway, compares the costs and outcome in 3 groups, one using a combination of an algorithm and patient/family education, a second using treatment as usual in a clinic that uses an algorithm for a different disorder, and a third using treatment as usual in a nonalgorithm clinic.

Clinical experience using gabapentin adjunctively in patients with a history of mania or hypomaniaJOURNAL OF AFFECTIVE DISORDERSKnoll, J., Stegman, K., Suppes, T.1998; 49 (3): 229-233

Abstract

Gabapentin is an anticonvulsant proposed to have mood-stabilizing properties. It has been effective in the add-on treatment of refractory partial seizures and secondary generalized tonic-clonic seizures. It has the advantage of a favorable side effect profile and lack of drug interactions.Twelve consecutive outpatients with persistent, treatment-resistant bipolar spectrum disorders were treated with gabapentin in combination with other medications. Patients were started at 300 mg/day, which was titrated according to clinical response. Response was assessed every 3-4 weeks with a Clinical Global Improvement Scale. Dosage and side effects were noted. The median peak dose was 2400 mg/day.One patient had a marked response to gabapentin; seven, a moderate response; two, mild; and two, no response to treatment. Six patients discontinued treatment due to somatic complaints (i.e., sedation or fatigue). The most frequently reported adverse effect was sedation.Gabapentin was added openly, and rating was nonblind in this case series. The use of concomitant medications could have increased the amount of sedation experienced with gabapentin.Overall, gabapentin was associated with moderate improvement of mood symptoms. Given the severity and chronicity of these patients' illness, a moderate response must be considered a relative success. Controlled studies of gabapentin are needed to clarify its role in the treatment of bipolar disorder.

Abstract

We evaluated the response to olanzapine in 14 consecutive patients with bipolar I disorder who were inadequately responsive to standard psychotropic agents.Fourteen patients with bipolar I disorder by DSM-IV criteria experiencing persistent affective symptoms inadequately responsive to at least one standard mood stabilizer were treated with open-label olanzapine by one of the authors. Response was assessed with the Clinical Global Impression Scale modified for use in bipolar disorder (CGI-BP).The 14 patients received olanzapine at a mean (SD dosage of 14.1+/-7.2 (range 5-30) mg/day for a mean+/-SD of 101.4+/-56.3 (range 30-217) days of treatment. Of the 14 patients, 8 (57%) displayed much or very much overall improvement in their illness. In general, olanzapine was well tolerated. The most common side effects were sedation, tremor, dry mouth, and appetite stimulation with weight gain.Data were obtained nonblindly and without a randomized control group, and olanzapine was added to ongoing psychotropic regimens.Olanzapine may have antimanic and mood-stabilizing effects in some patients with bipolar disorder, and is generally well tolerated. Controlled studies of olanzapine in bipolar disorder appear warranted.

Abstract

While monotherapy has significant limitations in bipolar disorder, few published data addressing alternatives exist. Treatment algorithms have been proposed, but none have undergone empirical evaluation. This study provides a systematic prospective, open evaluation of the effectiveness and tolerability of a treatment algorithm for patients with histories of mania.Twenty-eight symptomatic outpatients from a public mental health facility who were diagnosed as having either bipolar I or schizoaffective illness, bipolar type, entered the study. Minimum blood levels of lithium and divalproex sodium were defined. Medications were pushed to predetermined levels (as tolerated) before proceeding to the next algorithm step. Clinical symptoms were assessed monthly using the Brief Psychiatric Rating Scale (BPRS, 27 item) and Clinical Global Impressions scale.Pretreatment and posttreatment clinical symptoms were compared. Over 50% of patients attained 30% improvement from baseline BPRS after 4 months. Thirty-six percent of patients (N = 10) became mood stable, 46% (N = 13) remained mood unstable, and 18% (N = 5) dropped out before completing the algorithm. Although patients who finished the algorithm were taking more medication, either dosage and/or drugs, somatic complaints did not increase.The potential benefit of a defined treatment algorithm was demonstrated for these complex and persistently ill patients. Despite long treatment histories, patients improved with more frequent visits and addition of medication(s). A randomized controlled trial comparing a similar treatment algorithm with treatment-as-usual is warranted.

Abstract

This article presents two algorithms dealing with the management of schizophrenia. One provides a strategy for initiating pharmacologic treatment of schizophrenia and for ongoing medication management. The other covers suggestions for managing several common comorbid psychiatric conditions and some common side effects. The major change from previous algorithms is the suggestion that the newer atypical antipsychotic agents may now be the treatment of choice for initiating therapy in most clinical situations.

Abstract

Corticosteroids such as prednisone are commonly prescribed for a variety of illnesses mediated by the immune system. This paper reviews the available literature on mood symptoms during corticosteroid treatment. Few studies have used well-recognized measures of symptoms or clearly defined diagnostic criteria to characterize such mood changes. The limited data available suggest that symptoms of hypomania, mania, depression, and psychosis are common during therapy. Symptoms appear to be dose dependent and generally begin during the first few weeks of treatment. Risk factors for the development of mood instability or psychosis are not known. The similarities of the psychiatric symptoms resulting from corticosteroid treatment to the symptoms of bipolar disorder are discussed.

Abstract

Psychotic disorders are often difficult to treat with traditional neuroleptics. Sertindole is a new atypical neuroleptic with a broader CNS receptor profile.Ten patients diagnosed with either schizophrenia or schizoaffective disorder were treated with sertindole for 18 months and observed for changes in Clinical Global Impression scale scores.Nine patients experienced a reduction of symptoms after 12 months of treatment. Eight patients completed 18 months of treatment, all exhibiting overall improvement. Despite side effects of tiredness, weight gain, headache, nausea, and decreased ejaculatory volume, sertindole was generally well tolerated.Sertindole appears to be a useful treatment in psychotic disorders. It may present an advantage over traditional neuroleptics in the form of fewer extrapyramidal symptoms and improvement of negative symptoms.

Abstract

Electroconvulsive therapy (ECT) is an established effective treatment modality for patients with severe depression. Recent studies have focused on developing predictors of response. In this prospective study, using percent decrease in Hamilton Depression Scale (21 items) as the outcome measure, we blindly evaluated 33 inpatients with major depression to determine whether postictal suppression, the electrical silence following induced seizure, would predict treatment response to ECT. A significant relationship was observed between degree of postictal suppression and likelihood of clinical improvement. Postictal suppression should be explored in more controlled studies as a predictor of ECT response.

Abstract

Gradual discontinuation of lithium may reduce high risk of early morbidity in bipolar disorder patients discontinuing successful long-term maintenance on lithium, but previous small samples have limited analyses of subgroups.DSM-IV bipolar disorder patients (N = 161) were pooled from similar samples maintained on lithium for 4.2 +/- 3.1 years. Effects of discontinuing treatment abruptly (1-14 days) or gradually (15-30 days) were compared by survival analysis in clinically closely similar groups.After gradual versus rapid discontinuation, the overall median time to recurrence +/- SE differed by 5.0-fold (20.0 +/- 5.8 vs. 4.0 +/- 0.7 months; p < .0001). After rapid discontinuation, the median time in remission was 2.3 times shorter than the mean cycling interval before lithium (6.3 vs. 14.6 months; p < .0001). The proportion of subjects falling ill/month (recurrence rate) was much higher in the first year after rapid discontinuation (6.5% vs. 2.3%), but similar thereafter (0.4% vs. 0.6%); patients remained stable for 3 years when off lithium treatment 20 times more frequently after gradual than rapid discontinuation (37% vs. 1.8%; p < .0001). Ratios of median survival times after gradual/rapid lithium discontinuation were similar for a first recurrence of mania and depression (4.4 vs. 3.4-fold), insignificantly higher (34%) with rapid or continuous cycling before lithium, and greater in Type II than Type I disorder (9.8- vs. 4.0-fold). The polarity of first off-lithium and first lifetime episodes matched in 70% of cases.These pooled results strengthen the concept or a pharmacodynamic stress factor in early relapse after stopping lithium maintenance and support the conclusion that early recurrence risk can be minimized by discontinuing maintenance treatment gradually in both Type I and II bipolar disorders.

Abstract

Recent clinical research strongly suggests that there is a period of elevated risk of morbidity in the several months following abrupt discontinuation or reduction of doses in maintenance treatments commonly used in the contemporary management of chronic or recurring major psychiatric disorders. This risk is best quantified for the discontinuation of lithium therapy in bipolar disorders, in which risk of mania, depression, and suicidal behavior may rise. Similar symptomatic risks are well known after stopping antianxiety agents, and probably also follow rapid removal of oral neuroleptics in schizophenia and antidepressants in major depression. Morbid risk probably can be limited by slowing the rate of removal of medication. Such responses probably reflect interactions of individual illness diatheses with physiological adaptations to long-term drug treatments. The findings appear to have broad scientific, clinical, and ethical implications for clinical pharmacology in psychiatry as well as in general medicine.

Abstract

Bipolar disorder (BPD), probably the most prevalent psychotic disorder in adults, has been relatively neglected or controversial in children and adolescents over the past century. We reviewed the literature on early-onset BPD. Estimates of prevalence, particularly before puberty, are limited by historical biases against pediatric mood disorders and by formidable diagnostic complexity and comorbidity. Although clinical features of pediatric and adult BPD have similarities, pediatric cases probably cannot be defined solely by features characteristic of adult cases. Onset was before age 20 years in at least 25% of reported BPD cases, with some increase in this incidence over the past century. Pediatric BPD is familial more often than is adult-onset BPD, may be associated with a premorbid cyclothymic or hyperthymic temperament, and can be precipitated by antidepressant treatment. Pediatric BPD episodes frequently include irritability, dysphoria, or psychotic symptoms; they are commonly chronic and carry high risks of substance abuse and suicide. BPD is often recognized in adolescents, but the syndrome or its antecedents are almost certainly underrecognized and undertreated in children. Controlled studies of short- and long-term treatment, course, and outcome in this disorder remain strikingly limited, and the syndrome urgently requires increased clinical and scientific interest.

Abstract

The hypothesis that neurologic factors influence the response to valproate (divalproex sodium) in bipolar and schizoaffective disorders was tested. In 115 predominantly lithium-refractory inpatients, neurologic findings were recorded, and blind raters assessed valproate response from the medical record. Patients with a seizure history were much more likely to have a robust response to valproate (70%), when compared with patients without such history (34.6%). History of head injury and abnormal electroencephalographic findings also tended to be more common in those patients with good response. Overall, the group of patients with any neurologic abnormality exhibited a significantly higher rate of good response to valproate (43.6%) than did the neurologically normal group (24.3%). Bipolar or schizoaffective patients with abnormal neurologic features may represent a distinct subtype of illness and appear to be good candidates for valproate therapy.

STEREOTYPICAL CHANGES IN THE PATTERN AND DURATION OF LONG-TERM POTENTIATION EXPRESSED AT POSTNATAL DAYS 11 AND 15 IN THE RAT HIPPOCAMPUSJOURNAL OF NEUROPHYSIOLOGYJackson, P. S., Suppes, T., Harris, K. M.1993; 70 (4): 1412-1419

Abstract

1. Extracellular recordings from hippocampal area CA1 lasting 2-8 h posttetanus were used to evaluate the duration of long-term potentiation (LTP) at two key developmental ages. 2. At day 11 LTP consistently endured for approximately 1 h before declining to baseline by 2.5 h posttetanus. The response could then be repotentiated, and in some cases, the repotentiation lasted longer than the original potentiation. 3. At day 15 two patterns of potentiation were observed. The first pattern was similar to that observed at day 11 in that the potentiation did not persist; however, it did endure for approximately 2-2.5 h before declining to baseline by 4 h posttetanus. In the second pattern the potentiation persisted indefinitely; these responses were monitored for 6-8 h posttetanus. 4. These patterns are similar to the temporal phases of LTP that have been revealed in adult rat hippocampus through pharmacological manipulations. They may reflect developmental changes during which the different cellular mechanisms underlying LTP become sequentially activated. 5. These findings are important for several reasons. First, because the different temporal phases of LTP seem to be added stepwise during development, animals of different ages could be used explicitly to elucidate the underlying cellular mechanisms of these phases in LTP. Second, because LTP is a candidate mechanism for some forms of learning and memory, these results have implications for sequential steps in the ontogeny of learning and memory. Finally, because studies of LTP have used animals of widely varying ages, including these two ages, it is important to consider whether differences in the developmental properties of LTP could influence experimental observations.

Abstract

There is abundant evidence for substantial long-term prophylactic efficacy of lithium in bipolar manic-depressive disorders. Interruption of such treatment carries an extraordinarily high risk of recurrence within several months, even after several years of stability. Even a sharp reduction in dose may carry some risk. Gradual discontinuation of lithium was accompanied by markedly reduced risk of early recurrence. There is suggestive evidence that the phenomenon of high risk of recurrence after abrupt interruption of maintenance treatment may occur with other disorders and treatments, including neuroleptics in schizophrenia and possibly antidepressants in recurrent depression. The phenomenon of discontinuation-associated iatrogenic risk of early recurrence of major psychiatric illness has clear clinical implications. These include the need to evaluate safer methods of interrupting long-term maintenance treatment, particularly when clinical indications for rapid cessation are compelling and gradual discontinuation is not feasible. Questions also arise concerning interpretation of existing experimental studies of maintenance treatments that require interruption of treatment, reduction of dose, or crossover to a placebo, as well as the ethical and scientifically unambiguous design of future studies of this kind.

Abstract

Withdrawal of bipolar mood disorder (BP-I) patients from prolonged, stable lithium maintenance has a high risk of early recurrence, particularly of mania. We thus compared risks of stopping lithium rapidly vs gradually.Outpatients undergoing clinically determined discontinuation of lithium treatment at different rates were followed up prospectively to 5 years. Risks and timing of new episodes were analyzed.Subjects (N = 64) with a DSM-III-R BP disorder, previously stable on lithium monotherapy for 18 to 120 months (mean, 3.6 years) were followed up clinically after discontinuing lithium (elected in prolonged wellbeing in 67%). None was unavailable for follow-up, and subtyping (BP-I or BP-II) remained stable.Within 5 years, 75% had a recurrent episode; BP-I patients were 1.5-times less likely than BP-II to remain in remission. Polarity of first-recurrent and onset episodes was 80.8% concordant. Overall risk of a new episode of mania was significantly greater after rapid (< 2) than gradual (2 to 4 weeks discontinuation (5-year hazard ratio = 2.8); the difference in risk of depression was even greater hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 4.3) than at later times (2 to 5 years), when courses of "survival" over time were nearly parallel in both discontinuation groups.Risk of early recurrence of BP disorder following discontinuation of lithium maintenance is elevated, but may be both predictable (timing and polarity) and modifiable by gradual discontinuation.

Abstract

We reviewed consecutive patients (n = 12) at McLean Hospital from 1990 through 1991 treated with the combination of the atypical antipsychotic agent clozapine and electroconvulsive therapy (ECT). There were no adverse effects. Three patients had a marked clinical improvement, one a moderate response, four a minimal response, two minimal to no response, and two no response. Using daily doses of up to 550 mg clozapine, this combination appears to be safe, and may be useful in some patients with treatment-refractory psychosis.

Abstract

Seven patients with bipolar disorder, characterized by dysphoric mania with psychotic features and chronic disability, refractory to standard treatments and anticonvulsants, all showed marked symptomatic and functional improvement when given the atypical antipsychotic clozapine. During follow-up over 3-5 years, most of the patients sustained substantial gains in psychosocial function; and of the six patients remaining on clozapine, no further hospitalizations were needed. This remarkable improvement in a severely ill group of patients suggests that clozapine may have utility in the treatment of bipolar disorder as well as schizophrenia.

Abstract

Episode recurrence in bipolar disorder following discontinuation of stable maintenance treatment with lithium salts was analyzed from 14 studies involving 257 patients with bipolar I disorder. More than 50% of new episodes of illness occurred within 10 weeks of stopping an average of 30 months of treatment. By survival analysis of 124 cases in which the time to a new episode was known, the computed time to 50% failure of remission was 5.0 months after stopping therapy; the time to 25% recurrence of mania was 5.2 times earlier than for depression (2.7 vs 14 months). In 16 patients with a mean cycle length before treatment of 11.6 months, the time to a new episode when off lithium therapy was only 1.7 months. Risk of early recurrence of bipolar illness, especially of mania, evidently is increased following discontinuation of lithium use and may exceed that predicted by the course of the untreated disorder. The basis and management of risks associated with discontinuing effective long-term mood-stabilizing treatment require further study.

Abstract

The cellular and synaptic physiology of developing rat neocortical neurons was studied using the in vitro slice method. Rats aged 1-28 days were used for analysis. During the first two postnatal weeks several sequential changes occur in membrane properties and evoked synaptic potentials. Immature neurons had higher input resistances, more linear I-V characteristics, longer membrane time constants, and slower rising and falling phases of action potentials. The developmental increase in rate of rise of the action potential suggests an increasing density of voltage-dependent Na+-channels are inserted in neuronal membranes during postnatal development. The higher input resistance of young cells might be due to their small size and differences in membrane properties. The long time constant indicates a higher specific membrane resistivity of immature neurons. Postsynaptic potentials (PSPs) recorded in young neurons were longer in latency, longer in duration, and more fragile during repetitive activation than their mature counterparts. In addition, PSPs evoked in neurons of animals less than 1 week old did not contain inhibitory postsynaptic components. These physiological features of immature neocortical neurons help explain the pattern of epileptogenesis in young animals. When neonatal cortical slices were exposed to the gamma-aminobutyric acid (GABA) antagonists penicillin or bicuculline, the frequency of occurrence of discharges resembling epileptiform depolarization shifts approached that found in mature slices only during the second postnatal week. Depolarization shifts at younger ages were less stereotyped and more sensitive to stimulus parameters than those in mature neurons.

Abstract

The activity of neurones in the substantial nigra and ventral tegmentum was recorded extracellularly in vitro. Dopamine produced depression of spontaneous firing in a dose-dependent manner. Antagonism of these neuronal responses to dopamine by metoclopramide, SCH 23390 and clozapine was examined. Metoclopramide antagonised the responses to dopamine in the manner expected; SCH 23390 had little effect on the response to dopamine as would be predicted for a selective dopamine "D1" antagonist. Clozapine did not produce the expected antagonism of the response to dopamine. The results at the single neurone level are compared with behavioural and biochemical data.

Abstract

Dopamine (DA) application to guinea pig hippocampal CA1 neurons in vitro causes hyperpolarization of the resting potential, increase in conductance, and increase in amplitude and duration of the afterhyperpolarization (AHP). Since these changes could influence repetitive firing, we performed experiments to determine whether DA-induced effects would suppress epileptogenesis in the hippocampus. Epileptiform bursts were induced by adding penicillin (3.4 mM) to the perfusion medium. Focal application of DA (40-160 microns) onto CA1 cells (n = 15) produced a hyperpolarization averaging 4.5 mV beginning in 5-20 s and lasting up to 3 min. DA also caused an increase in the amplitude and duration of slow AHPs. The frequency of spontaneous epileptiform events however was not affected. CA3 neurons (n = 6) responded to DA application with an initial 1-3 mV depolarization beginning within 5-30 s and lasting 1-2 min. In 3 cases a small hyperpolarization lasting several minutes subsequently developed. AHP duration increased 70% and amplitude increased 35% (n = 4). Along with these membrane changes the frequency of epileptiform bursting in CA3 cells slowed for 1-3 min. We added DA (10-80 microM) to the perfusion medium to see whether a significant decrease in epileptiform burst frequency might occur in the follower CA1 region if greater numbers of pacemaker CA2 and CA3 cells were exposed to DA. Spontaneous CA1 bursting was reversibly slowed, the interburst interval became variable and increased from a mean of 4 to a mean of 5-7 s (n = 6). These results suggest that DA may play a role in decreasing the incidence or frequency of epileptogenic discharges in vivo.

Abstract

Neonatal rat superior cervical ganglia were mechanically dissociated, and the sympathetic neurons grown in dispersed cell cultures. Intracellular microelectrodes were used to study the effects of tetraethylammonium (TEA+), a blocker of outward K+ currents, on the excitable properties of these neurons. Addition of TEA+ to the perfusion media (TEA+-media) caused the resting potential to depolarize and the action potential to increase in duration. In TEA+-media (20-60 mM), a late delayed depolarization (LDD) followed the falling phase of the action potential with a delay of 1.5-2 s (n = 95). The LDD peak amplitude was in the range of 4-26 mV and the duration, to full return of the resting potential, was in the range of 18-90 s. For a given cell the amplitude and duration of the LDD were constant. The LDD was associated with a conductance increase. No LDD could be elicited in the presence of calcium channel blockers. Evidence was found for a Ca2+-dependence of the LDD: increasing the extracellular Ca2+ concentration caused increases in the amplitude and duration of the LDD. The significance of an endogenous LDD-like potential and possible explanations for the origin of the LDD are discussed.

Abstract

Acetylcholine (1-20 mM) was applied to guinea pig hippocampal slices bathed in normal and penicillin-containing media. Recordings in the CA 1 pyramidal cell layer in the presence of penicillin showed that acetylcholine caused a prolonged enhancement of the extracellular field potential. Intracellular recordings documented an increase in duration of cell bursting, a decrease in burst afterhyperpolarization, and a membrane depolarization lasting 1-5 min. These results suggest that the actions of acetylcholine to increase membrane excitability interact with penicillin-induced disinhibition to enhance hippocampal epileptogenesis.